Publications by authors named "Robert H Henning"

136 Publications

Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation.

Front Physiol 2021 1;12:624950. Epub 2021 Apr 1.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their 'great slumbers.'
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http://dx.doi.org/10.3389/fphys.2021.624950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047423PMC
April 2021

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney.

Redox Biol 2021 Apr 2;43:101961. Epub 2021 Apr 2.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Hydrogen sulfide (HS) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, HS is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. HS-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, HS is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of HS are not precisely understood. HS modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, HS affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by HS. HS enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of HS anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal HS levels. Together, HS is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of HS not only expands fundamental insight in the regulation of functional effects mediated by HS, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.
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http://dx.doi.org/10.1016/j.redox.2021.101961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065217PMC
April 2021

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney.

Redox Biol 2021 Apr 2;43:101961. Epub 2021 Apr 2.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Hydrogen sulfide (HS) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, HS is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. HS-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, HS is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of HS are not precisely understood. HS modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, HS affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by HS. HS enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of HS anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal HS levels. Together, HS is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of HS not only expands fundamental insight in the regulation of functional effects mediated by HS, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.
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http://dx.doi.org/10.1016/j.redox.2021.101961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065217PMC
April 2021

Reversible thrombocytopenia during hibernation originates from storage and release of platelets in liver sinusoids.

J Comp Physiol B 2021 May 4;191(3):603-615. Epub 2021 Mar 4.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Immobility is a risk factor for thrombosis due to low blood flow, which may result in activation of the coagulation system, recruitment of platelets and clot formation. Nevertheless, hibernating animals-who endure lengthy periods of immobility-do not show signs of thrombosis throughout or after hibernation. One of the adaptations of hemostasis in hibernators consists of a rapidly reversible reduction of the number of circulating platelets during torpor, i.e., the hibernation phase with reduction of metabolic rate, low blood flow and immobility. It is unknown whether these platelet dynamics in hibernating hamsters originate from storage and release, as suggested for ground squirrel, or from breakdown and de novo synthesis. A reduction in detaching forces due to low blood flow can induce reversible adhesion of platelets to the vessel wall, which is called margination. Here, we hypothesized that storage-and-release by margination to the vessel wall induces reversible thrombocytopenia in torpor. Therefore, we transfused labeled platelets in hibernating Syrian hamster (Mesocricetus auratus) and platelets were analyzed using flow cytometry and electron microscopy. The half-life of labeled platelets was extended from 20 to 30 h in hibernating animals compared to non-hibernating control hamsters. More than 90% of labeled platelets were cleared from the circulation during torpor, followed by emergence during arousal which supports storage-and-release to govern thrombocytopenia in torpor. Furthermore, the low number of immature platelets, plasma level of interleukin-1α and normal numbers of megakaryocytes in bone marrow make platelet synthesis or megakaryocyte rupture via interleukin-1α unlikely to account for the recovery of platelet counts upon arousal. Finally, using large-scale electron microscopy we revealed platelets to accumulate in liver sinusoids, but not in spleen or lung, during torpor. These results thus demonstrate that platelet dynamics in hibernation are caused by storage and release of platelets, most likely by margination to the vessel wall in liver sinusoids. Translating the molecular mechanisms that govern platelet retention in the liver, may be of major relevance for hemostatic management in (accidental) hypothermia and for the development of novel anti-thrombotic strategies.
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http://dx.doi.org/10.1007/s00360-021-01351-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043940PMC
May 2021

Ensemble machine learning prediction and variable importance analysis of 5-year mortality after cardiac valve and CABG operations.

Sci Rep 2021 Feb 10;11(1):3467. Epub 2021 Feb 10.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Despite having a similar post-operative complication profile, cardiac valve operations are associated with a higher mortality rate compared to coronary artery bypass grafting (CABG) operations. For long-term mortality, few predictors are known. In this study, we applied an ensemble machine learning (ML) algorithm to 88 routinely collected peri-operative variables to predict 5-year mortality after different types of cardiac operations. The Super Learner algorithm was trained using prospectively collected peri-operative data from 8241 patients who underwent cardiac valve, CABG and combined operations. Model performance and calibration were determined for all models, and variable importance analysis was conducted for all peri-operative parameters. Results showed that the predictive accuracy was the highest for solitary mitral (0.846 [95% CI 0.812-0.880]) and solitary aortic (0.838 [0.813-0.864]) valve operations, confirming that ensemble ML using routine data collected perioperatively can predict 5-year mortality after cardiac operations with high accuracy. Additionally, post-operative urea was identified as a novel and strong predictor of mortality for several types of operation, having a seemingly additive effect to better known risk factors such as age and postoperative creatinine.
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http://dx.doi.org/10.1038/s41598-021-82403-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876023PMC
February 2021

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms.

Front Physiol 2020 20;11:623665. Epub 2021 Jan 20.

Department of Biology, Carleton University, Ottawa, ON, Canada.

Torpor and hibernation are powerful strategies enabling animals to survive periods of low resource availability. The state of torpor results from an active and drastic reduction of an individual's metabolic rate (MR) associated with a relatively pronounced decrease in body temperature. To date, several forms of torpor have been described in all three mammalian subclasses, i.e., monotremes, marsupials, and placentals, as well as in a few avian orders. This review highlights some of the characteristics, from the whole organism down to cellular and molecular aspects, associated with the torpor phenotype. The first part of this review focuses on the specific metabolic adaptations of torpor, as it is used by many species from temperate zones. This notably includes the endocrine changes involved in fat- and food-storing hibernating species, explaining biomedical implications of MR depression. We further compare adaptive mechanisms occurring in opportunistic vs. seasonal heterotherms, such as tropical and sub-tropical species. Such comparisons bring new insights into the metabolic origins of hibernation among tropical species, including resistance mechanisms to oxidative stress. The second section of this review emphasizes the mechanisms enabling heterotherms to protect their key organs against potential threats, such as reactive oxygen species, associated with the torpid state. We notably address the mechanisms of cellular rehabilitation and protection during torpor and hibernation, with an emphasis on the brain, a central organ requiring protection during torpor and recovery. Also, a special focus is given to the role of an ubiquitous and readily-diffusing molecule, hydrogen sulfide (HS), in protecting against ischemia-reperfusion damage in various organs over the torpor-arousal cycle and during the torpid state. We conclude that (i) the flexibility of torpor use as an adaptive strategy enables different heterothermic species to substantially suppress their energy needs during periods of severely reduced food availability, (ii) the torpor phenotype implies marked metabolic adaptations from the whole organism down to cellular and molecular levels, and (iii) the torpid state is associated with highly efficient rehabilitation and protective mechanisms ensuring the continuity of proper bodily functions. Comparison of mechanisms in monotremes and marsupials is warranted for understanding the origin and evolution of mammalian torpor.
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http://dx.doi.org/10.3389/fphys.2020.623665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854925PMC
January 2021

Phase specific suppression of neutrophil function in hibernating Syrian hamster.

Dev Comp Immunol 2021 Jun 24;119:104024. Epub 2021 Jan 24.

Department Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Internal Medicine, Section Acute Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address:

Hibernation consists of alternating periods of reduced metabolism (torpor) with brief periods of metabolism similar to summer euthermia (arousal). The function of the innate immune system is reduced during hibernation, of which the underlying mechanisms are incompletely understood. Here, we studied neutrophil functionality during hibernation in Syrian hamsters. The inflammatory response to LPS-induced endotoxemia is inhibited in hibernation, partly mediated by reduced IL-6 production in early arousal. Furthermore, neutrophil pathogen binding, phagocytosis and oxidative burst is profoundly reduced in early arousal. Functionality of both summer and early arousal neutrophils was repressed in plasma from early arousal and mixed plasma from early arousal and summer euthermic, but restored by summer euthermic plasma, signifying that a plasma factor in early arousal inhibits TLR-recognition. Identification of the inhibiting factor may offer a target to modulate neutrophil function with relevance to (auto-)inflammatory diseases.
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http://dx.doi.org/10.1016/j.dci.2021.104024DOI Listing
June 2021

Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI.

Crit Care 2021 01 25;25(1):36. Epub 2021 Jan 25.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, EB70, 9700 RB, Groningen, The Netherlands.

Background: Sepsis is a life-threatening condition accompanied by organ dysfunction subsequent to a dysregulated host response to infection. Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. The pathophysiology of sepsis-associated AKI (sepsis-AKI) remains incompletely understood, but mitochondria have emerged as key players in the pathogenesis. Therefore, our aim was to identify mitochondrial damage in patients with sepsis-AKI.

Methods: We conducted a clinical laboratory study using "warm" postmortem biopsies from sepsis-associated AKI patients from a university teaching hospital. Biopsies were taken from adult patients (n = 14) who died of sepsis with AKI at the intensive care unit (ICU) and control patients (n = 12) undergoing tumor nephrectomy. To define the mechanisms of the mitochondrial contribution to the pathogenesis of sepsis-AKI, we explored mRNA and DNA expression of mitochondrial quality mechanism pathways, DNA oxidation and mitochondrial DNA (mtDNA) integrity in renal biopsies from sepsis-AKI patients and control subjects. Next, we induced human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS) for 48 h to mimic sepsis and validate our results in vitro.

Results: Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. Sepsis-AKI patients had lower mRNA expression of mitochondrial quality markers TFAM, PINK1 and PARKIN, but not of MFN2 and DRP1. Oxidative DNA damage was present in the cytosol of tubular epithelial cells in the kidney of sepsis-AKI patients, whereas it was almost absent in biopsies from control subjects. Oxidative DNA damage co-localized with both the nuclei and mitochondria. Accordingly, HUVECs induced with LPS for 48 h showed an increased mnSOD expression, a decreased TFAM expression and higher mtDNA damage levels.

Conclusion: Sepsis-AKI induces mitochondrial DNA damage in the human kidney, without upregulation of mitochondrial quality control mechanisms, which likely resulted in a reduction in mitochondrial mass.
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http://dx.doi.org/10.1186/s13054-020-03424-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831178PMC
January 2021

Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells.

Int J Mol Sci 2020 Mar 9;21(5). Epub 2020 Mar 9.

Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

Mitochondrial failure is recognized to play an important role in a variety of diseases. We previously showed hibernating species to have cell-autonomous protective mechanisms to resist cellular stress and sustain mitochondrial function. Here, we set out to detail these mitochondrial features of hibernators. We compared two hibernator-derived cell lines (HaK and DDT1MF2) with two non-hibernating cell lines (HEK293 and NRK) during hypothermia (4 °C) and rewarming (37 °C). Although all cell lines showed a strong decrease in oxygen consumption upon cooling, hibernator cells maintained functional mitochondria during hypothermia, without mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential decline or decreased adenosine triphosphate (ATP) levels, which were all observed in both non-hibernator cell lines. In addition, hibernator cells survived hypothermia in the absence of extracellular energy sources, suggesting their use of an endogenous substrate to maintain ATP levels. Moreover, hibernator-derived cells did not accumulate reactive oxygen species (ROS) damage and showed normal cell viability even after 48 h of cold-exposure. In contrast, non-hibernator cells accumulated ROS and showed extensive cell death through ferroptosis. Understanding the mechanisms that hibernators use to sustain mitochondrial activity and counteract damage in hypothermic circumstances may help to define novel preservation techniques with relevance to a variety of fields, such as organ transplantation and cardiac arrest.
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http://dx.doi.org/10.3390/ijms21051864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084219PMC
March 2020

Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation.

Cells 2019 10 5;8(10). Epub 2019 Oct 5.

Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HV Amsterdam, The Netherlands.

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and ) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target.
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http://dx.doi.org/10.3390/cells8101202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829298PMC
October 2019

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation.

J Transl Med 2019 08 13;17(1):265. Epub 2019 Aug 13.

Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.

Background: Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. However, the exact effect of hypothermic kidney preservation on mitochondrial function remains unclear.

Methods: We evaluated mitochondrial function [i.e. oxygen consumption and production of reactive oxygen species (ROS)] in different models (porcine kidney perfusion, isolated kidney mitochondria, and HEK293 cells) at temperatures ranging 7-37 °C.

Results: Lowering temperature in perfused kidneys and isolated mitochondria resulted in a rapid decrease in oxygen consumption (65% at 27 °C versus 20% at 7 °C compared to normothermic). Decreased oxygen consumption at lower temperatures was accompanied by a reduction in mitochondrial ROS production, albeit markedly less pronounced and amounting only 50% of normothermic values at 7 °C. Consequently, malondialdehyde (a marker of ROS-induced lipid peroxidation) accumulated in cold stored kidneys. Similarly, low temperature incubation of kidney cells increased lipid peroxidation, which is due to a loss of ROS scavenging in the cold.

Conclusions: Lowering of temperature highly affects mitochondrial function, resulting in a progressive discrepancy between the lowering of mitochondrial respiration and their production of ROS, explaining the deleterious effects of hypothermia in transplantation procedures. These results highlight the necessity to develop novel strategies to decrease the formation of ROS during hypothermic organ preservation.
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http://dx.doi.org/10.1186/s12967-019-2013-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693148PMC
August 2019

Gasotransmitters in health and disease: a mitochondria-centered view.

Curr Opin Pharmacol 2019 04 17;45:87-93. Epub 2019 Jul 17.

Department of Pathology and Medical Biology, Pathology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Gasotransmitters fulfill important roles in cellular homeostasis having been linked to various pathologies, including inflammation and cardiovascular diseases. In addition to the known pathways mediating the actions of gasotransmitters, their effects in regulating mitochondrial function are emerging. Given that mitochondria are key organelles in energy production, formation of reactive oxygen species and apoptosis, they are important mediators in preserving health and disease. Preserving or restoring mitochondrial function by gasotransmitters may be beneficial, and mitigate pathogenetic processes. In this review we discuss the actions of gasotransmitters with focus on their role in mitochondrial function and their therapeutic potential.
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http://dx.doi.org/10.1016/j.coph.2019.07.001DOI Listing
April 2019

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD depletion in experimental atrial fibrillation.

Nat Commun 2019 03 21;10(1):1307. Epub 2019 Mar 21.

Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ, Amsterdam, The Netherlands.

Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD), induces further DNA damage and contractile dysfunction. Accordingly, NAD replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.
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http://dx.doi.org/10.1038/s41467-019-09014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428932PMC
March 2019

Screening of novel HSP-inducing compounds to conserve cardiomyocyte function in experimental atrial fibrillation.

Drug Des Devel Ther 2019 18;13:345-364. Epub 2019 Jan 18.

Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands,

Background: The heat shock protein (HSP) inducer, geranylgeranylacetone (GGA), was previously found to protect against atrial fibrillation (AF) remodeling in experimental model systems. Clinical application of GGA in AF is limited, due to low systemic concentrations owing to the hydrophobic character of GGA.

Objectives: To identify novel HSP-inducing compounds, with improved physicochemical properties, that prevent contractile dysfunction in experimental model systems for AF.

Methods: Eighty-one GGA-derivatives were synthesized and explored for their HSP-inducing properties by assessment of HSP expression in HL-1 cardiomyocytes pretreated with or without a mild heat shock (HS), followed by incubation with 10 µM GGA or GGA-derivative. Subsequently, the most potent HSP-inducers were tested for preservation of calcium transient (CaT) amplitudes or heart wall contraction in pretreated tachypaced HL-1 cardiomyocytes (with or without HSPB1 siRNA) and , respectively. Finally, CaT recovery in tachypaced HL-1 cardiomyocytes posttreated with GGA or protective GGA-derivatives was determined.

Results: Thirty GGA-derivatives significantly induced HSPA1A expression after HS, and seven showed exceeding HSPA1A expression compared to GGA. GGA and nine GGA-derivatives protected significantly from tachypacing (TP)-induced CaT loss, which was abrogated by HSPB1 suppression. GGA and four potent GGA-derivatives protected against heart wall dysfunction after TP compared to non-paced control . Of these compounds, GGA and three GGA-derivatives induced a significant restoration from CaT loss after TP of HL-1 cardiomyocytes.

Conclusion: We identified novel GGA-derivatives with improved physicochemical properties compared to GGA. GGA-derivatives, particularly GGA-59, boost HSP expression resulting in prevention and restoration from TP-induced remodeling, substantiating their role as novel therapeutics in clinical AF.
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http://dx.doi.org/10.2147/DDDT.S176924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342224PMC
June 2019

Metabolic Resuscitation Strategies to Prevent Organ Dysfunction in Sepsis.

Antioxid Redox Signal 2019 07 23;31(2):134-152. Epub 2019 Jan 23.

1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Sepsis is the main cause of death among patients admitted to the intensive care unit. As current treatment is limited to antimicrobial therapy and supportive care, mortality remains high, which warrants efforts to find novel therapies. Mitochondrial dysfunction is emerging as a key process in the induction of organ dysfunction during sepsis, and metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. Here, we review novel strategies to maintain organ function in sepsis by precluding mitochondrial dysfunction by lowering energetic demand to allow preservation of adenosine triphosphate-levels, while reducing free radical generation. As the most common strategy to suppress metabolism, that is, cooling, does not reveal unequivocal beneficial effects and may even increase mortality, caloric restriction or modulation of energy-sensing pathways (, sirtuins and AMP-activated protein kinase) may offer safe alternatives. Similar effects may be offered when mimicking hibernation by hydrogen sulfide (HS). In addition HS may also confer beneficial effects through upregulation of antioxidant mechanisms, similar to the other gasotransmitters nitric oxide and carbon monoxide, which display antioxidant and anti-inflammatory effects in sepsis. In addition, oxidative stress may be averted by systemic or mitochondria-targeted antioxidants, of which a wide range are able to lower inflammation, as well as reduce organ dysfunction and mortality from sepsis. Mitochondrial dysfunction plays a key role in the pathophysiology of sepsis. As a consequence, metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis.
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http://dx.doi.org/10.1089/ars.2018.7537DOI Listing
July 2019

Converse role of class I and class IIa HDACs in the progression of atrial fibrillation.

J Mol Cell Cardiol 2018 12 12;125:39-49. Epub 2018 Oct 12.

Department of Physiology, Amsterdam UMC, Amsterdam Cardiovascular Sciences, Vrije Universiteit Amsterdam, the Netherlands. Electronic address:

Atrial fibrillation (AF), the most common persistent clinical tachyarrhythmia, is associated with altered gene transcription which underlies cardiomyocyte dysfunction, AF susceptibility and progression. Recent research showed class I and class IIa histone deacetylases (HDACs) to regulate pathological and fetal gene expression, and thereby induce hypertrophy and cardiac contractile dysfunction. Whether class I and class IIa HDACs are involved in AF promotion is unknown. We aim to elucidate the role of class I and class IIa HDACs in tachypacing-induced contractile dysfunction in experimental model systems for AF and clinical AF. METHODS AND RESULTS: Class I and IIa HDACs were overexpressed in HL-1 cardiomyocytes followed by calcium transient (CaT) measurements. Overexpression of class I HDACs, HDAC1 or HDAC3, significantly reduced CaT amplitude in control normal-paced (1 Hz) cardiomyocytes, which was further reduced by tachypacing (5 Hz) in HDAC3 overexpressing cardiomyocytes. HDAC3 inhibition by shRNA or by the specific inhibitor, RGFP966, prevented contractile dysfunction in both tachypaced HL-1 cardiomyocytes and Drosophila prepupae. Conversely, overexpression of class IIa HDACs (HDAC4, HDAC5, HDAC7 or HDAC9) did not affect CaT in controls, with HDAC5 and HDAC7 overexpression even protecting against tachypacing-induced CaT loss. Notably, the protective effect of HDAC5 and HDAC7 was abolished in cardiomyocytes overexpressing a dominant negative HDAC5 or HDAC7 mutant, bearing a mutation in the binding domain for myosin enhancer factor 2 (MEF2). Furthermore, tachypacing induced phosphorylation of HDAC5 and promoted its translocation from the nucleus to cytoplasm, leading to up-regulation of MEF2-related fetal gene expression (β-MHC, BNP). In accord, boosting nuclear localization of HDAC5 by MC1568 or Go6983 attenuated CaT loss in tachypaced HL-1 cardiomyocytes and preserved contractile function in Drosophila prepupae. Findings were expanded to clinical AF. Here, patients with AF showed a significant increase in expression levels and activity of HDAC3, phosphorylated HDAC5 and fetal genes (β-MHC, BNP) in atrial tissue compared to controls in sinus rhythm. CONCLUSION: Class I and class IIa HDACs display converse roles in AF progression. Whereas overexpression of Class I HDAC3 induces cardiomyocyte dysfunction, class IIa HDAC5 overexpression reveals protective properties. Accordingly, HDAC3 inhibitors and HDAC5 nuclear boosters show protection from tachypacing-induced changes and therefore may represent interesting therapeutic options in clinical AF.
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http://dx.doi.org/10.1016/j.yjmcc.2018.09.010DOI Listing
December 2018

Reply.

Ann Thorac Surg 2018 12 11;106(6):1891-1892. Epub 2018 Aug 11.

Department of Anesthesiology, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.athoracsur.2018.07.006DOI Listing
December 2018

Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling.

Heart Rhythm 2018 11 11;15(11):1708-1716. Epub 2018 Jun 11.

Department of Clinical Pharmacy and Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands. Electronic address:

Background: Dysregulation of protein kinase-mediated signaling is an early event in many diseases, including the most common clinical cardiac arrhythmia, atrial fibrillation (AF). Kinomic profiling represents a promising technique to identify candidate kinases.

Objective: In this study we used kinomic profiling to identify kinases altered in AF remodeling using atrial tissue from a canine model of AF (atrial tachypacing).

Methods: Left atrial tissue obtained in a previous canine study was used for kinomic array (containing 1024 kinase pseudosubstrates) analysis. Three groups of dogs were included: nonpaced controls and atrial tachypaced dogs, which were contrasted with geranylgeranylacetone-treated dogs with AF, which are protected from AF promotion, to enhance specificity of detection of putative kinases.

Results: While tachypacing changed activity of 50 kinases, 40 of these were prevented by geranylgeranylacetone and involved in differentiation and proliferation (SRC), contraction, metabolism, immunity, development, cell cycle (CDK4), and survival (Akt). Inhibitors of Akt (MK2206) and CDK4 (PD0332991) and overexpression of a dominant-negative CDK4 phosphorylation mutant protected against tachypacing-induced contractile dysfunction in HL-1 cardiomyocytes. Moreover, patients with AF show down- and upregulation of SRC and Akt phosphorylation, respectively, similar to findings of the kinome array.

Conclusion: Contrasting kinomic array analyses of controls and treated subjects offer a versatile tool to identify kinases altered in atrial remodeling owing to tachypacing, which include Akt, CDK4, and SRC. Ultimately, pharmacological targeting of altered kinases may offer novel therapeutic possibilities to treat clinical AF.
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http://dx.doi.org/10.1016/j.hrthm.2018.06.014DOI Listing
November 2018

Torpor-arousal cycles in Syrian hamster heart are associated with transient activation of the protein quality control system.

Comp Biochem Physiol B Biochem Mol Biol 2018 09 9;223:23-28. Epub 2018 Jun 9.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.

Hibernation consists of torpor, with marked suppression of metabolism and physiological functions, alternated with arousal periods featuring their full restoration. The heart is particularly challenged, exemplified by its rate reduction from 400 to 5-10 beats per minute during torpor in Syrian hamsters. In addition, during arousals, the heart needs to accommodate the very rapid return to normal function, which lead to our hypothesis that cardiac function during hibernation is supported by maintenance of protein homeostasis through adaptations in the protein quality control (PQC) system. Hereto, we examined autophagy, the endoplasmic reticulum (ER) unfolded protein (UPR) response and the heat shock response (HSR) in Syrian hamster hearts during torpor and arousal. Transition from torpor to arousal (1.5 h) was associated with stimulation of the PQC system during early arousal, demonstrated by induction of autophagosomes, as shown by an increase in LC3B-II protein abundance, likely related to the activation of the UPR during late torpor in response to proteotoxic stress. The HSR was not activated during torpor or arousal. Our results demonstrate activation of the cardiac PQC system - particularly autophagosomal degradation - in early arousal in response to cardiac stress, to clear excess aberrant or damaged proteins, being gradually formed during the torpor bout and/or the rapid increase in heart rate during the transition from torpor to arousal. This mechanism may enable the large gain in cardiac function during the transition from torpor to arousal, which may hold promise to further understand 'hibernation' of cardiomyocytes in human heart disease.
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http://dx.doi.org/10.1016/j.cbpb.2018.06.001DOI Listing
September 2018

The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats.

Nephrol Dial Transplant 2018 12;33(12):2128-2138

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats.

Methods: Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 µg/kg/h) undergoing H/R at 15°C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed.

Results: H/R injury in vitro lowered cell viability by 94 ± 1%, which was counteracted dose-dependently by multiple 6-hydroxychomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 5'-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation.

Conclusions: The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols limit DNA damage, but only SUL-109 also prevented protein nitrosylation in tubular cells. Therefore SUL-109 offers a promising therapeutic strategy to preserve kidney mitochondrial function.
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http://dx.doi.org/10.1093/ndt/gfy080DOI Listing
December 2018

Acute Kidney Injury Classification Underestimates Long-Term Mortality After Cardiac Valve Operations.

Ann Thorac Surg 2018 07 1;106(1):92-98. Epub 2018 Mar 1.

Department of Anesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands.

Background: Perioperative acute kidney injury (AKI) is an important predictor of long-term all-cause mortality after coronary artery bypass (CABG). However, the effect of AKI on long-term mortality after cardiac valve operations is hitherto undocumented.

Methods: Perioperative renal injury and long-term all-cause mortality after valve operations were studied in a prospective cohort of patients undergoing solitary valve operations (n = 2,806) or valve operations combined with CABG (n = 1,260) with up to 18 years of follow-up. Postoperative serum creatinine increase was classified according to AKI staging 0 to 3. Patients undergoing solitary CABG (n = 4,938) with cardiopulmonary bypass served as reference.

Results: In both valve and valve+CABG operations, postoperative renal injury of AKI stage 1 or higher was progressively associated with an increase in long-term mortality (hazard ratio [HR], 2.27, p < 0.05 for valve; HR, 1.65, p < 0.05 for valve+CABG; HR, 1.56, p < 0.05 for CABG). Notably, the mortality risk increased already substantially at serum creatinine increases of 10% to 25%-that is, far below the threshold for AKI stage 1 after valve operations (HR, 1.39, p < 0.05), but not after valve operations combined with CABG or CABG only.

Conclusions: An increase in serum creatinine by more than 10% during the first week after valve operation is associated with an increased risk for long-term mortality after cardiac valve operation. Thus, AKI classification clearly underestimates long-term mortality risk in patients undergoing valve operations.
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http://dx.doi.org/10.1016/j.athoracsur.2018.01.066DOI Listing
July 2018

Gastrointestinal tuberculosis following renal transplantation accompanied with septic shock and acute respiratory distress syndrome: a survival case presentation.

BMC Gastroenterol 2017 Nov 28;17(1):131. Epub 2017 Nov 28.

University Hospital Bratislava, Nemocnica Ruzinov, ICU, KAIM, Clinic of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

Background: Post-transplant tuberculosis (PTTB) is a serious opportunistic infection in renal graft recipients with a 30-70 fold higher incidence compared to the general population. PTTB occurs most frequently within the first years after transplantation, manifesting as pulmonary or disseminated TB. Gastrointestinal TB (GITB) is a rare and potentially lethal manifestation of PTTB and may show delayed onset in renal transplant recipients due to the use of lower doses of immunosuppressants. Further, non-specificity of symptoms and the common occurrence of GI disorders in transplant recipients may delay diagnosis of GITB.

Case Presentation: Here we report a rare survival case of isolated GITB in a renal transplant recipient, occurring seven years after transplantation. The patient's condition was complicated by severe sepsis with positive blood culture Staphylococcus haemolyticus, septic shock, multiple organ failure including acute respiratory distress syndrome (ARDS) and acute renal failure, requiring mechanical ventilation, vasopressor circulatory support and intermittent hemodialysis. Furthermore, nosocomial infections such as invasive aspergillosis and Pseudomonas aeruginosa occurred during hospitalization. Antituberculosis therapy (rifampicin, isoniazid, ethambutol and pyrazinamide) was initiated upon Mycobacterium confirmation. Moreover, treatment with voriconazole due to the Aspergillus flavus and meropenem due to the Pseudomonas aeruginosa was initiated, the former necessitating discontinuation of rifampicin. After 34 days, the patient was weaned from mechanical ventilation and was discharged to the pulmonary ward, followed by complete recovery.

Conclusion: This case offers a guideline for the clinical management towards survival of GITB in transplant patients, complicated by septic shock and multiple organ failure, including acute renal injury and ARDS.
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http://dx.doi.org/10.1186/s12876-017-0695-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704353PMC
November 2017

Differences in mitochondrial function and morphology during cooling and rewarming between hibernator and non-hibernator derived kidney epithelial cells.

Sci Rep 2017 11 14;7(1):15482. Epub 2017 Nov 14.

Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Hibernators show superior resistance to ischemia and hypothermia, also outside the hibernation season. Therefore, hibernation is a promising strategy to decrease cellular damage in a variety of fields, such as organ transplantation. Here, we explored the role of mitochondria herein, by comparing epithelial cell lines from a hibernator (hamster kidney cells, HaK) and a non-hibernator (human embryonic kidney cells, HEK293) during cold preservation at 4 °C and rewarming. Cell survival (Neutral Red), ATP and MDA levels, mitochondrial membrane potential (MMP), mitochondrial morphology (using fluorescent probes) and metabolism (seahorse XF) were assessed. Hypothermia induced dispersion of the tubular mitochondrial network, a loss of MMP, increased oxygen radical (MDA) and decreased ATP production in HEK293. In contrast, HaK maintained MMP and ATP production without an increase in oxygen radicals during cooling and rewarming, resulting in superior cell survival compared to HEK293. Further, normothermic HaK showed a dispersed mitochondrial network and higher respiratory and glycolysis capacity compared to HEK293. Disclosing the mechanisms that hibernators use to counteract cell death in hypothermic and ischemic circumstances may help to eventually improve organ preservation in a variety of fields, including organ transplantation.
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http://dx.doi.org/10.1038/s41598-017-15606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686174PMC
November 2017

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation.

J Am Heart Assoc 2017 Oct 24;6(10). Epub 2017 Oct 24.

Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands

Background: Derailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self-perpetuating nature of atrial fibrillation (AF), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF.

Methods And Results: Tachypacing of HL-1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC3B-II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca amplitude. Autophagy is activated downstream of endoplasmic reticulum (ER) stress: blocking ER stress by the chemical chaperone 4-phenyl butyrate, overexpression of the ER chaperone-protein heat shock protein A5, or overexpression of a phosphorylation-blocked mutant of eukaryotic initiation factor 2α (eIF2α) prevents autophagy activation and Ca-transient loss in tachypaced HL-1 cardiomyocytes. Moreover, pharmacological inhibition of ER stress in tachypaced confirms its role in derailing cardiomyocyte function. In vivo treatment with sodium salt of phenyl butyrate protected atrial-tachypaced dog cardiomyocytes from electrical remodeling (action potential duration shortening, L-type Ca-current reduction), cellular Ca-handling/contractile dysfunction, and ER stress and autophagy; it also attenuated AF progression. Finally, atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage.

Conclusions: These results identify ER stress-associated autophagy as an important pathway in AF progression and demonstrate the potential therapeutic action of the ER-stress inhibitor 4-phenyl butyrate.
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http://dx.doi.org/10.1161/JAHA.117.006458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721854PMC
October 2017

Metformin Improves Endothelial Function and Reduces Blood Pressure in Diabetic Spontaneously Hypertensive Rats Independent from Glycemia Control: Comparison to Vildagliptin.

Sci Rep 2017 09 8;7(1):10975. Epub 2017 Sep 8.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Metformin confers vascular benefits beyond glycemia control, possibly via pleiotropic effects on endothelial function. In type-1-diabetes-mellitus (T1DM-)patients metformin improved flow-mediated dilation but also increased prostaglandin(PG)-F, a known endothelial-contracting factor. To explain this paradoxical finding we hypothesized that metformin increased endothelial-vasodilator mediators (e.g. NO and EDHF) to an even larger extent. Spontaneously-hypertensive-rats (SHR) display impaired endothelium-dependent relaxation (EDR) involving contractile PGs. EDR was studied in isolated SHR aortas and the involvement of PGs, NO and EDHF assessed. 12-week metformin 300 mg/kg/day improved EDR by up-regulation of NO and particularly EDHF; it also reduced blood pressure and increased plasma sulphide levels (a proxy for HS, a possible mediator of EDHF). These effects persisted in SHR with streptozotocin (STZ)-induced T1DM. Vildagliptin (10 mg/kg/day), targeting the incretin axis by increasing GLP-1, also reduced blood pressure and improved EDR in SHR aortas, mainly via the inhibition of contractile PGs, but not in STZ-SHR. Neither metformin nor vildagliptin altered blood glucose or HbA. In conclusion, metformin reduced blood pressure and improved EDR in SHR aorta via up-regulation of NO and particularly EDHF, an effect that was independent from glycemia control and maintained during T1DM. A comparison to vildagliptin did not support effects of metformin mediated by GLP-1.
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http://dx.doi.org/10.1038/s41598-017-11430-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591199PMC
September 2017

A Hibernation-Like State for Transplantable Organs: Is Hydrogen Sulfide Therapy the Future of Organ Preservation?

Antioxid Redox Signal 2018 06 29;28(16):1503-1515. Epub 2017 Aug 29.

3 Matthew Mailing Center for Translational Transplant Studies, Western University , London, Canada .

Significance: Renal transplantation is the treatment of choice for end-stage renal disease, during which renal grafts from deceased donors are routinely cold stored to suppress metabolic demand and thereby limit ischemic injury. However, prolonged cold storage, followed by reperfusion, induces extensive tissue damage termed cold ischemia/reperfusion injury (IRI) and puts the graft at risk of both early and late rejection. Recent Advances: Deep hibernators constitute a natural model of coping with cold IRI as they regularly alternate between 4°C and 37°C. Recently, endogenous hydrogen sulfide (HS), a gas with a characteristic rotten egg smell, has been implicated in organ protection in hibernation.

Critical Issues: In renal transplantation, HS also seems to confer cytoprotection by lowering metabolism, thereby creating a hibernation-like environment, and increasing preservation time while allowing cellular processes of preservation of homeostasis and tissue remodeling to take place, thus increasing renal graft survival.

Future Directions: Although the underlying cellular and molecular mechanisms of organ protection during hibernation have not been fully explored, mammalian hibernation may offer a great clinical promise to safely cold store and reperfuse donor organs. In this review, we first discuss mammalian hibernation as a natural model of cold organ preservation with reference to the kidney and highlight the involvement of HS during hibernation. Next, we present recent developments on the protective effects and mechanisms of exogenous and endogenous HS in preclinical models of transplant IRI and evaluate the potential of HS therapy in organ preservation as great promise for renal transplant recipients in the future. Antioxid. Redox Signal. 28, 1503-1515.
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http://dx.doi.org/10.1089/ars.2017.7127DOI Listing
June 2018

Proteostasis in cardiac health and disease.

Nat Rev Cardiol 2017 Nov 29;14(11):637-653. Epub 2017 Jun 29.

Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing. Failure of protein quality control involves impairment of chaperones, ubiquitin-proteosomal systems, autophagy, and loss of sarcomeric and cytoskeletal proteins, all of which relate to induction of cardiomyocyte senescence. Targeting protein quality control to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease. Currently marketed drugs are available to explore this concept in the clinical setting.
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http://dx.doi.org/10.1038/nrcardio.2017.89DOI Listing
November 2017

Predictive Properties of Biomarkers GDF-15, NTproBNP, and hs-TnT for Morbidity and Mortality in Patients With Type 2 Diabetes With Nephropathy.

Diabetes Care 2017 06 24;40(6):784-792. Epub 2017 Mar 24.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

Objective: Although patients with type 2 diabetes (T2D) with nephropathy are at high risk for renal and cardiovascular complications, relevant biomarkers have been poorly identified. Because renal impairment may increase biomarker levels, this potentially confounds associations between biomarker levels and risk. To investigate the predictive value of a biomarker in such a setting, we examined baseline levels of growth differentiation factor-15 (GDF-15), N-terminal prohormone of B-type natriuretic peptide (NTproBNP), and high-sensitivity troponin T (hs-TnT) in relation to renal and cardiovascular risk in T2D patients with nephropathy.

Research Design And Methods: Eight hundred sixty-one T2D patients from the sulodexide macroalbuminuria (Sun-MACRO) trial were included in our post hoc analysis. Prospective associations of baseline serum GDF-15, NTproBNP, and hs-TnT with renal and cardiovascular events were determined by Cox multiple regression and C-statistic analysis. Renal base models included albumin-to-creatinine ratio (ACR), serum creatinine, hemoglobin, age, and sex. Cardiovascular base models included diastolic blood pressure, ACR, cholesterol, age, and sex.

Results: The mean (±SD) estimated glomerular filtration rate was 33 ± 9 mL/min/1.73 m, and the median serum concentration for GDF-15 was 3,228 pg/mL (interquartile range 2,345-4,310 pg/mL), for NTproBNP was 380 ng/L (155-989 ng/L), and for hs-TnT was 30 ng/L (20-47 ng/L). In multiple regression analysis, GDF-15 (hazard ratio [HR] 1.83, = 0.04), NTproBNP (HR 2.34, = 0.004), and hs-TnT (HR 2.09, = 0.014) were associated with renal events, whereas NTproBNP (HR 3.45, < 0.001) was associated with cardiovascular events. The C-statistic was improved by adding NTproBNP and hs-TNT to the renal model (0.793 vs. 0.741, = 0.04). For cardiovascular events, the C-statistic was improved by adding NTproBNP alone (0.722 vs. 0.658, = 0.018).

Conclusions: Biomarkers GDF-15, NTproBNP, and hs-TnT associate independently with renal risk, whereas NTproBNP independently predicts cardiovascular risk.
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http://dx.doi.org/10.2337/dc16-2175DOI Listing
June 2017

The influence of sex and diet on the characteristics of hibernation in Syrian hamsters.

J Comp Physiol B 2017 Jul 21;187(5-6):725-734. Epub 2017 Mar 21.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Research on deep hibernators almost exclusively uses species captured from the wild or from local breeding. An exception is Syrian hamster (Mesocricetus auratus), the only standard laboratory animal showing deep hibernation. In deep hibernators, several factors influence hibernation quality, including body mass, sex and diet. We examined hibernation quality in commercially obtained Syrian hamsters in relation to body mass, sex and a diet enriched in polyunsaturated fatty acids. Animals (M/F:30/30, 12 weeks of age) were obtained from Harlan (IN, USA) and individually housed at 21 °C and L:D 14:10 until 20 weeks of age, followed by L:D 8:16 until 27 weeks. Then conditions were changed to 5 °C and L:D 0:24 for 9 weeks to induce hibernation. Movement was continuously monitored with passive infrared detectors. Hamsters were randomized to control diet or a diet 3× enriched in linoleic acid from 16 weeks of age. Hamsters showed a high rate of premature death (n = 24, 40%), both in animals that did and did not initiate torpor, which was unrelated to body weight, sex and diet. Time to death (31.7 ± 3.1 days, n = 12) or time to first torpor bout (36.6 ± 1.6 days, n = 12) was similar in prematurely deceased hamsters. Timing of induction of hibernation and duration of torpor and arousal was unaffected by body weight, sex or diet. Thus, commercially obtained Syrian hamsters subjected to winter conditions showed poor survival, irrespective of body weight, sex and diet. These factors also did not affect hibernation parameters. Possibly, long-term commercial breeding from a confined genetic background has selected against the hibernation trait.
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http://dx.doi.org/10.1007/s00360-017-1072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486544PMC
July 2017

Renal Mitochondrial Response to Low Temperature in Non-Hibernating and Hibernating Species.

Antioxid Redox Signal 2017 Sep 26;27(9):599-617. Epub 2017 Apr 26.

1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands .

Significance: Therapeutic hypothermia is commonly applied to limit ischemic injury in organ transplantation, during cardiac and brain surgery and after cardiopulmonary resuscitation. In these procedures, the kidneys are particularly at risk for ischemia/reperfusion injury (IRI), likely due to their high rate of metabolism. Although hypothermia mitigates ischemic kidney injury, it is not a panacea. Residual mitochondrial failure is believed to be a key event triggering loss of cellular homeostasis, and potentially cell death. Subsequent rewarming generates large amounts of reactive oxygen species that aggravate organ injury. Recent Advances: Hibernators are able to withstand periods of profoundly reduced metabolism and body temperature ("torpor"), interspersed by brief periods of rewarming ("arousal") without signs of organ injury. Specific adaptations allow maintenance of mitochondrial homeostasis, limit oxidative stress, and protect against cell death. These adaptations consist of active suppression of mitochondrial function and upregulation of anti-oxidant enzymes and anti-apoptotic pathways.

Critical Issues: Unraveling the precise molecular mechanisms that allow hibernators to cycle through torpor and arousal without precipitating organ injury may translate into novel pharmacological approaches to limit IRI in patients.

Future Directions: Although the precise signaling routes involved in natural hibernation are not yet fully understood, torpor-like hypothermic states with increased resistance to ischemia/reperfusion can be induced pharmacologically by 5'-adenosine monophosphate (5'-AMP), adenosine, and hydrogen sulfide (HS) in non-hibernators. In this review, we compare the molecular effects of hypothermia in non-hibernators with natural and pharmacologically induced torpor, to delineate how safe and reversible metabolic suppression may provide resistance to renal IRI. Antioxid. Redox Signal. 27, 599-617.
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http://dx.doi.org/10.1089/ars.2016.6705DOI Listing
September 2017