Publications by authors named "Sergio Lavandero"

252 Publications

Left Cardiac Remodelling Assessed by Echocardiography Is Associated with Rho-Kinase Activation in Long-Distance Runners.

J Cardiovasc Dev Dis 2021 Sep 24;8(10). Epub 2021 Sep 24.

Advanced Center for Chronic Diseases (ACCDiS), Division of Cardiovascular Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Av. Sergio Livingstone #1007, Santiago 8380492, Chile.

This single-blind and cross-sectional study evaluated the role of Rho-kinase (ROCK) as a biomarker of the cardiovascular remodelling process assessed by echocardiography in competitive long-distance runners (LDRs) during the training period before a marathon race. Thirty-six healthy male LDRs (37.0 ± 5.3 years; 174.0 ± 7.0 height; BMI: 23.8 ± 2.8; V˙ O-peak: 56.5 ± 7.3 mL·kg·min) were separated into two groups according to previous training level: high-training (HT, = 16) ≥ 100 km·week and low-training (LT, = 20) ≥ 70 and < 100 km·week. Also, twenty-one healthy nonactive subjects were included as a control group (CTR). A transthoracic echocardiography was performed and ROCK activity levels in circulating leukocytes were measured at rest (48 h without exercising) the week before the race. The HT group showed a higher left ventricular mass index (LVMi) and left atrial volume index (LAVi) than other groups ( < 0.05, for both); also, higher levels of ROCK activity were found in LDRs (HT = 6.17 ± 1.41 vs. CTR = 1.64 ± 0.66 ( < 0.01); vs. LT = 2.74 ± 0.84; ( < 0.05)). In LDRs a direct correlation between ROCK activity levels and LVMi (r = 0.83; < 0.001), and LAVi (r = 0.70; < 0.001) were found. In conclusion, in male competitive long-distance runners, the load of exercise implicated in marathon training is associated with ROCK activity levels and the left cardiac remodelling process assessed by echocardiography.
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http://dx.doi.org/10.3390/jcdd8100118DOI Listing
September 2021

Skeletal muscle type-specific mitochondrial adaptation to high-fat diet relies on differential autophagy modulation.

FASEB J 2021 10;35(10):e21933

Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile.

In obesity, skeletal muscle mitochondrial activity changes to cope with increased nutrient availability. Autophagy has been proposed as an essential mechanism involved in the regulation of mitochondrial metabolism. Still, the contribution of autophagy to mitochondrial adaptations in skeletal muscle during obesity is unknown. Here, we show that in response to high-fat diet (HFD) feeding, distinct skeletal muscles in mice exhibit differentially regulated autophagy that may modulate mitochondrial activity. We observed that after 4 and 40 weeks of high-fat diet feeding, OXPHOS subunits and mitochondrial DNA content increased in the oxidative soleus muscle. However, in gastrocnemius muscle, which has a mixed fiber-type composition, the mitochondrial mass increased only after 40 weeks of HFD feeding. Interestingly, fatty acid-supported mitochondrial respiration was enhanced in gastrocnemius, but not in soleus muscle after a 4-week HFD feeding. This increased metabolic profile in gastrocnemius was paralleled by preserving autophagy flux, while autophagy flux in soleus was reduced. To determine the role of autophagy in this differential response, we used an autophagy-deficient mouse model with partial deletion of Atg7 specifically in skeletal muscle (SkM-Atg7 mice). We observed that Atg7 reduction resulted in diminished autophagic flux in skeletal muscle, alongside blunting the HFD-induced increase in fatty acid-supported mitochondrial respiration observed in gastrocnemius. Remarkably, SkM-Atg7 mice did not present increased mitochondria accumulation. Altogether, our results show that HFD triggers specific mitochondrial adaptations in skeletal muscles with different fiber type compositions, and that Atg7-mediated autophagy modulates mitochondrial respiratory capacity but not its content in response to an obesogenic diet.
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http://dx.doi.org/10.1096/fj.202001593RRDOI Listing
October 2021

Polycystin-1 is required for insulin-like growth factor 1-induced cardiomyocyte hypertrophy.

PLoS One 2021 18;16(8):e0255452. Epub 2021 Aug 18.

Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile and Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.

Cardiac hypertrophy is the result of responses to various physiological or pathological stimuli. Recently, we showed that polycystin-1 participates in cardiomyocyte hypertrophy elicited by pressure overload and mechanical stress. Interestingly, polycystin-1 knockdown does not affect phenylephrine-induced cardiomyocyte hypertrophy, suggesting that the effects of polycystin-1 are stimulus-dependent. In this study, we aimed to identify the role of polycystin-1 in insulin-like growth factor-1 (IGF-1) signaling in cardiomyocytes. Polycystin-1 knockdown completely blunted IGF-1-induced cardiomyocyte hypertrophy. We then investigated the molecular mechanism underlying this result. We found that polycystin-1 silencing impaired the activation of the IGF-1 receptor, Akt, and ERK1/2 elicited by IGF-1. Remarkably, IGF-1-induced IGF-1 receptor, Akt, and ERK1/2 phosphorylations were restored when protein tyrosine phosphatase 1B was inhibited, suggesting that polycystin-1 knockdown deregulates this phosphatase in cardiomyocytes. Moreover, protein tyrosine phosphatase 1B inhibition also restored IGF-1-dependent cardiomyocyte hypertrophy in polycystin-1-deficient cells. Our findings provide the first evidence that polycystin-1 regulates IGF-1-induced cardiomyocyte hypertrophy through a mechanism involving protein tyrosine phosphatase 1B.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255452PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372926PMC
August 2021

Resolvin-D1 attenuation of angiotensin II-induced cardiac inflammation in mice is associated with prevention of cardiac remodeling and hypertension.

Biochim Biophys Acta Mol Basis Dis 2021 Dec 13;1867(12):166241. Epub 2021 Aug 13.

Department of Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address:

Aims: Despite the broad pharmacological arsenal to treat hypertension, chronic patients may develop irreversible cardiac remodeling and fibrosis. Angiotensin II, the main peptide responsible for the Renin-Angiotensin-Aldosterone-System, has been closely linked to cardiac remodeling, hypertrophy, fibrosis, and hypertension, and some of these effects are induced by inflammatory mediators. Resolvin-D1 (RvD1) elicits potent anti-inflammatory and pro-resolving effects in various pathological models. In this study, we aimed to examine whether RvD1 ameliorates cardiac remodeling and hypertension triggered by angiotensin II.

Methods And Results: Alzet® osmotic mini-pumps filled with angiotensin II (1.5 mg/kg/day) were implanted in male C57BL/6 J mice for 7 or 14 days. RvD1 (3 μg/kg/day, i.p) was administered one day after the surgery and during the complete infusion period. Blood pressure and myocardial functional parameters were assessed by echocardiography. At the end of the experimental procedure, blood and heart tissue were harvested, and plasma and histological parameters were studied. After 7 and 14 days, RvD1 reduced the increase of neutrophil and macrophage infiltration triggered by angiotensin II, and also reduced ICAM-1 and VCAM-1 expression levels. RvD1 also reduced cytokine plasma levels (IL-1β, TNF-α, IL-6, KC, MCP-1), cardiac hypertrophy, interstitial and perivascular fibrosis, and hypertension.

Conclusions: This study unveils novel cardioprotective effects of RvD1 in angiotensin II-induced hypertension and cardiac remodeling by attenuating inflammation and provides insights into a potential clinical application.
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http://dx.doi.org/10.1016/j.bbadis.2021.166241DOI Listing
December 2021

Polycystin-1 regulates cardiomyocyte mitophagy.

FASEB J 2021 08;35(8):e21796

Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Polycystin-1 (PC1) is a transmembrane protein found in different cell types, including cardiomyocytes. Alterations in PC1 expression have been linked to mitochondrial damage in renal tubule cells and in patients with autosomal dominant polycystic kidney disease. However, to date, the regulatory role of PC1 in cardiomyocyte mitochondria is not well understood. The analysis of mitochondrial morphology from cardiomyocytes of heterozygous PC1 mice (PDK1 ) using transmission electron microscopy showed that cardiomyocyte mitochondria were smaller with increased mitochondria density and circularity. These parameters were consistent with mitochondrial fission. We knocked-down PC1 in cultured rat cardiomyocytes and human-induced pluripotent stem cells (iPSC)-derived cardiomyocytes to evaluate mitochondrial function and morphology. The results showed that downregulation of PC1 expression results in reduced protein levels of sub-units of the OXPHOS complexes and less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production). This mitochondrial dysfunction activates the elimination of defective mitochondria by mitophagy, assessed by an increase of autophagosome adapter protein LC3B and the recruitment of the Parkin protein to the mitochondria. siRNA-mediated PC1 knockdown leads to a loss of the connectivity of the mitochondrial network and a greater number of mitochondria per cell, but of smaller sizes, which characterizes mitochondrial fission. PC1 silencing also deregulates the AKT-FoxO1 signaling pathway, which is involved in the regulation of mitochondrial metabolism, mitochondrial morphology, and processes that are part of cell quality control, such as mitophagy. Together, these data provide new insights about the controls that PC1 exerts on mitochondrial morphology and function in cultured cardiomyocytes dependent on the AKT-FoxO1 signaling pathway.
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http://dx.doi.org/10.1096/fj.202002598RDOI Listing
August 2021

Endoplasmic reticulum-mitochondria coupling increases during doxycycline-induced mitochondrial stress in HeLa cells.

Cell Death Dis 2021 06 28;12(7):657. Epub 2021 Jun 28.

Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Subcellular organelles communicate with each other to regulate function and coordinate responses to changing cellular conditions. The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER-mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial-ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C/EBPβ, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2 h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca uptake. This was followed by the rise in the rate of oxygen consumption at 4 h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial-ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.
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http://dx.doi.org/10.1038/s41419-021-03945-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238934PMC
June 2021

Novel molecular insights and public omics data in pulmonary hypertension.

Biochim Biophys Acta Mol Basis Dis 2021 Oct 16;1867(10):166200. Epub 2021 Jun 16.

Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago 8380492, Chile; Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Electronic address:

Pulmonary hypertension is a rare disease with high morbidity and mortality which mainly affects women of reproductive age. Despite recent advances in understanding the pathogenesis of pulmonary hypertension, the high heterogeneity in the presentation of the disease among different patients makes it difficult to make an accurate diagnosis and to apply this knowledge to effective treatments. Therefore, new studies are required to focus on translational and personalized medicine to overcome the lack of specificity and efficacy of current management. Here, we review the majority of public databases storing 'omics' data of pulmonary hypertension studies, from animal models to human patients. Moreover, we review some of the new molecular mechanisms involved in the pathogenesis of pulmonary hypertension, including non-coding RNAs and the application of 'omics' data to understand this pathology, hoping that these new approaches will provide insights to guide the way to personalized diagnosis and treatment.
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http://dx.doi.org/10.1016/j.bbadis.2021.166200DOI Listing
October 2021

VCAM-1 as a predictor biomarker in cardiovascular disease.

Biochim Biophys Acta Mol Basis Dis 2021 Sep 14;1867(9):166170. Epub 2021 May 14.

Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

The vascular cellular adhesion molecule-1 (VCAM-1) is a protein that canonically participates in the adhesion and transmigration of leukocytes to the interstitium during inflammation. VCAM-1 expression, together with soluble VCAM-1 (sVCAM-1) induced by the shedding of VCAM-1 by metalloproteinases, have been proposed as biomarkers in immunological diseases, cancer, autoimmune myocarditis, and as predictors of mortality and morbidity in patients with chronic heart failure (HF), endothelial injury in patients with coronary artery disease, and arrhythmias. This revision aims to discuss the role of sVCAM-1 as a biomarker to predict the occurrence, development, and preservation of cardiovascular disease.
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http://dx.doi.org/10.1016/j.bbadis.2021.166170DOI Listing
September 2021

The role of autophagy in cardiovascular pathology.

Cardiovasc Res 2021 May 6. Epub 2021 May 6.

Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.

Macroautophagy/autophagy is a conserved catabolic recycling pathway in which cytoplasmic components are sequestered, degraded, and recycled to survive various stress conditions. Autophagy dysregulation has been observed and linked with the development and progression of several pathologies, including cardiovascular diseases, the leading cause of death in the developed world. In this review, we aim to provide a broad understanding of the different molecular factors that govern autophagy regulation and how these mechanisms are involved in the development of specific cardiovascular pathologies, including ischemic and reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiac remodeling, and heart failure.
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http://dx.doi.org/10.1093/cvr/cvab158DOI Listing
May 2021

NAD Repletion Reverses Heart Failure With Preserved Ejection Fraction.

Circ Res 2021 May 22;128(11):1629-1641. Epub 2021 Apr 22.

Internal Medicine (Cardiology) (D.T., G.G.S., N.J., F.A., P.A.S., A.E., H.Y., L.I.S., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas, TX.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159891PMC
May 2021

Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy.

Circulation 2021 Jul 6;144(1):34-51. Epub 2021 Apr 6.

Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas.

Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK (mitogen-activated protein kinase)/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. How these pathways interact remains unclear and few direct targets responsible for the prohypertrophic role of NFAT have been described.

Methods: By engineering cardiomyocyte-specific ETS2 (a member of the E26 transformation-specific sequence [ETS] domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were used to evaluate ETS2 function in cell growth.

Results: ETS2 is phosphorylated and activated by Erk1/2 on hypertrophic stimulation in both mouse (n=3) and human heart samples (n=8 to 19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n=6 to 11). Silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n=8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as , , and (n=4). We report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least 2 hypertrophy-stimulated genes: and microRNA-223 (=n4 to 6). Suppression of microRNA-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n=6), revealing microRNA-223 as a novel prohypertrophic target of the calcineurin/NFAT and Erk1/2-ETS2 pathways.

Conclusions: Our findings point to a critical role for ETS2 in calcineurin/NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247545PMC
July 2021

Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.

Nat Commun 2021 03 16;12(1):1684. Epub 2021 Mar 16.

Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA.

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.
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http://dx.doi.org/10.1038/s41467-021-21931-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966396PMC
March 2021

Perspectives on Organelle Interaction, Protein Dysregulation, and Cancer Disease.

Front Cell Dev Biol 2021 25;9:613336. Epub 2021 Feb 25.

Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile.

In recent decades, compelling evidence has emerged showing that organelles are not static structures but rather form a highly dynamic cellular network and exchange information through membrane contact sites. Although high-throughput techniques facilitate identification of novel contact sites (e.g., organelle-organelle and organelle-vesicle interactions), little is known about their impact on cellular physiology. Moreover, even less is known about how the dysregulation of these structures impacts on cellular function and therefore, disease. Particularly, cancer cells display altered signaling pathways involving several cell organelles; however, the relevance of interorganelle communication in oncogenesis and/or cancer progression remains largely unknown. This review will focus on organelle contacts relevant to cancer pathogenesis. We will highlight specific proteins and protein families residing in these organelle-interfaces that are known to be involved in cancer-related processes. First, we will review the relevance of endoplasmic reticulum (ER)-mitochondria interactions. This section will focus on mitochondria-associated membranes (MAMs) and particularly the tethering proteins at the ER-mitochondria interphase, as well as their role in cancer disease progression. Subsequently, the role of Ca at the ER-mitochondria interphase in cancer disease progression will be discussed. Members of the Bcl-2 protein family, key regulators of cell death, also modulate Ca transport pathways at the ER-mitochondria interphase. Furthermore, we will review the role of ER-mitochondria communication in the regulation of proteostasis, focusing on the ER stress sensor PERK (PRKR-like ER kinase), which exerts dual roles in cancer. Second, we will review the relevance of ER and mitochondria interactions with other organelles. This section will focus on peroxisome and lysosome organelle interactions and their impact on cancer disease progression. In this context, the peroxisome biogenesis factor (PEX) gene family has been linked to cancer. Moreover, the autophagy-lysosome system is emerging as a driving force in the progression of numerous human cancers. Thus, we will summarize our current understanding of the role of each of these organelles and their communication, highlighting how alterations in organelle interfaces participate in cancer development and progression. A better understanding of specific organelle communication sites and their relevant proteins may help to identify potential pharmacological targets for novel therapies in cancer control.
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http://dx.doi.org/10.3389/fcell.2021.613336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946981PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Targeting the Endothelium to Achieve Cardioprotection.

Front Pharmacol 2021 2;12:636134. Epub 2021 Feb 2.

Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Despite considerable improvements in the treatment of myocardial infarction, it is still a highly prevalent disease worldwide. Novel therapeutic strategies to limit infarct size are required to protect myocardial function and thus, avoid heart failure progression. Cardioprotection is a research topic with significant achievements in the context of basic science. However, translation of the beneficial effects of protective approaches from bench to bedside has proven difficult. Therefore, there is still an unmet need to study new avenues leading to protecting the myocardium against infarction. In line with this, the endothelium is an essential component of the cardiovascular system with multiple therapeutic targets with cardioprotective potential. Endothelial cells are the most abundant non-myocyte cell type in the heart and are key players in cardiovascular physiology and pathophysiology. These cells can regulate vascular tone, angiogenesis, hemostasis, and inflammation. Accordingly, endothelial dysfunction plays a fundamental role in cardiovascular diseases, which may ultimately lead to myocardial infarction. The endothelium is of paramount importance to protect the myocardium from ischemia/reperfusion injury via conditioning strategies or cardioprotective drugs. This review will provide updated information on the most promising therapeutic agents and protective approaches targeting endothelial cells in the context of myocardial infarction.
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http://dx.doi.org/10.3389/fphar.2021.636134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884828PMC
February 2021

Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy.

Biol Res 2021 Feb 5;54(1). Epub 2021 Feb 5.

Programa de Fisiología Y Biofísica, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, 8389100, Independencia, Santiago, Chile.

Background: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR).

Methods: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR).

Results: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated β-mhc, Hk2 and Pfk2 mRNA levels.

Conclusion: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
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http://dx.doi.org/10.1186/s40659-021-00328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863443PMC
February 2021

Manipulation of ACE2 expression in COVID-19.

Open Heart 2020 12;7(2)

Department of Emergency Medicine and Integrative Biosciences Center, Wayne State University School of Medicine, Detroit, Michigan, USA.

SARS-CoV-2 is the virus responsible for the ongoing COVID-19 outbreak. The virus uses ACE2 receptor for viral entry. ACE2 is part of the counter-regulatory renin-angiotensin-aldosterone system and is also expressed in the lower respiratory tract along the alveolar epithelium. There is, however, significant controversy regarding the role of ACE2 expression in COVID-19 pathogenesis. Some have argued that decreasing ACE2 expression would result in decreased susceptibility to the virus by decreasing available binding sites for SARS-CoV-2 and restricting viral entry into the cells. Others have argued that, like the pathogenesis of other viral pneumonias, including those stemming from previous severe acute respiratory syndrome (SARS) viruses, once SARS-CoV-2 binds to ACE2, it downregulates ACE2 expression. Lack of the favourable effects of ACE2 might exaggerate lung injury by a variety of mechanisms. In order to help address this controversy, we conducted a literature search and review of relevant preclinical and clinical publications pertaining to SARS-CoV-2, COVID-19, ACE2, viral pneumonia, SARS, acute respiratory distress syndrome and lung injury. Our review suggests, although controversial, that patients at increased susceptibility to COVID-19 complications may have reduced baseline ACE2, and by modulating ACE2 expression one can possibly improve COVID-19 outcomes. Herein, we elucidate why and how this potential mechanism might work.
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http://dx.doi.org/10.1136/openhrt-2020-001424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757413PMC
December 2020

Role of Autophagy in the Microenvironment of Oral Squamous Cell Carcinoma.

Front Oncol 2020 9;10:602661. Epub 2020 Dec 9.

Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas & Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Oral squamous cell carcinoma, the most common type of oral cancer, affects more than 275,000 people per year worldwide. Oral squamous cell carcinoma is very aggressive, as most patients die after 3 to 5 years post-diagnosis. The initiation and progression of oral squamous cell carcinoma are multifactorial: smoking, alcohol consumption, and human papilloma virus infection are among the causes that promote its development. Although oral squamous cell carcinoma involves abnormal growth and migration of oral epithelial cells, other cell types such as fibroblasts and immune cells form the carcinoma niche. An underlying inflammatory state within the oral tissue promotes differential stress-related responses that favor oral squamous cell carcinoma. Autophagy is an intracellular degradation process that allows cancer cells to survive under stress conditions. Autophagy degrades cellular components by sequestering them in vesicles called autophagosomes, which ultimately fuse with lysosomes. Although several autophagy markers have been associated with oral squamous cell carcinoma, it remains unclear whether up- or down-regulation of autophagy favors its progression. Autophagy levels during oral squamous cell carcinoma are both timing- and cell-specific. Here we discuss how autophagy is required to establish a new cellular microenvironment in oral squamous cell carcinoma and how autophagy drives the phenotypic change of oral squamous cell carcinoma cells by promoting crosstalk between carcinoma cells, fibroblasts, and immune cells.
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http://dx.doi.org/10.3389/fonc.2020.602661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756113PMC
December 2020

Light-induced release of the cardioprotective peptide angiotensin-(1-9) from thermosensitive liposomes with gold nanoclusters.

J Control Release 2020 12 4;328:859-872. Epub 2020 Nov 4.

Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceúticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile; Departamento de Química Farmacológica y Toxicológica, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile; Corporación Centro de Estudios Científicos de las Enfermedades Crónicas (CECEC), Santiago 7680201, Chile. Electronic address:

Angiotensin-(1-9), a component of the non-canonical renin-angiotensin system, has a short half-life in blood. This peptide has shown to prevent and/or attenuate hypertension and cardiovascular remodeling. A controlled release of angiotensin-(1-9) is needed for its delivery to the heart. Our aim was to develop a drug delivery system for angiotensin-(1-9). Thermosensitive liposomes (LipoTherm) were prepared with gold nanoclusters (LipoTherm-AuNC) to increase the stability and reach a temporal and spatial control of angiotensin-(1-9) release. Encapsulation efficiencies of nearly 50% were achieved in LipoTherm, reaching a total angiotensin-(1-9) loading of around 180 μM. This angiotensin-(1-9)-loaded LipoTherm sized around 100 nm and exhibited a phase transition temperature of 43 °C. AuNC were grown on LipoTherm and the new hybrid nanosystem showed energy absorption in the near-infrared (NIR) wavelength range. By NIR laser irradiation, a controlled release of angiotensin-(1-9) was achieved from the LipoTherm-AuNC nanosystem. These nanosystems did not show any cytotoxic effect on cultured cardiomyocytes. Biological activity of angiotensin-(1-9) released from the LipoTherm-AuNC-based nanosystem was confirmed using an ex vivo Langendorff heart model.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.002DOI Listing
December 2020

Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function.

Circulation 2020 Dec 28;142(24):2356-2370. Epub 2020 Oct 28.

Division of Cardiology, Department of Internal Medicine (S.Y.K., G.G.S., F.A., K.M.F., N.J., P.A.S., H.I.M., X.L., L.I.S., S.L., T.G.G., J.A.H.), University of Texas Southwestern, Dallas.

Background: BET (bromodomain and extraterminal) epigenetic reader proteins, in particular BRD4 (bromodomain-containing protein 4), have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small-molecule BET protein inhibitors such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BET proteins in the heart have not been conducted to validate pharmacological findings and to unveil potential pharmacological side effects.

Methods: By engineering a cardiomyocyte-specific BRD4 knockout mouse, we investigated the role of BRD4 in cardiac pathophysiology. We performed functional, transcriptomic, and mitochondrial analyses to evaluate BRD4 function in developing and mature hearts.

Results: Unlike pharmacological inhibition, loss of BRD4 protein triggered progressive declines in myocardial function, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse heart tissue identified early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria from these hearts confirmed that BRD4 ablation triggered significant changes in mitochondrial electron transport chain protein expression and activity. Computational analysis identified candidate transcription factors participating in the BRD4-regulated transcriptome. In particular, estrogen-related receptor α, a key nuclear receptor in metabolic gene regulation, was enriched in promoters of BRD4-regulated mitochondrial genes.

Conclusions: In aggregate, we describe a previously unrecognized role for BRD4 in regulating cardiomyocyte mitochondrial homeostasis, observing that its function is indispensable to the maintenance of normal cardiac function.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736324PMC
December 2020

Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy.

Int J Mol Sci 2020 Oct 15;21(20). Epub 2020 Oct 15.

Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago 7830490, Chile.

Autophagy is upregulated in adipose tissue (AT) from people with obesity. We showed that activation of the calcium-sensing receptor (CaSR) elevates proinflammatory cytokines through autophagy in preadipocytes. Our aim is to understand the role of CaSR on autophagy in AT from humans with obesity. We determined mRNA and protein levels of CaSR and markers of autophagy by qPCR and western blot in human visceral AT explants or isolated primary preadipocytes (60 donors: 72% female, 23-56% body fat). We also investigated their association with donors' anthropometric variables. Donors' % body fat and CaSR mRNA expression in AT were correlated (r = 0.44, < 0.01). CaSR expression was associated with mRNA levels of the autophagy markers (r = 0.37, < 0.01), (r = 0.29, < 0.05) and (r = 0.40, < 0.01). CaSR activation increased and mRNA expression in AT. CaSR activation also upregulated LC3II by ~50%, an effect abolished by the CaSR inhibitor. Spermine (CaSR agonist) regulates LC3II through the ERK1/2 pathway. Structural equation model analysis suggests a link between donors' AT CaSR expression, AT autophagy and expression of Tumor Necrosis Factor alpha TNF-α. CaSR expression in visceral AT is directly associated with % body fat, and CaSR activation may contribute to obesity-related disruption in AT autophagy.
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http://dx.doi.org/10.3390/ijms21207617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590196PMC
October 2020

Vaccines against components of the renin-angiotensin system.

Heart Fail Rev 2021 May 29;26(3):711-726. Epub 2020 Sep 29.

Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Medicina Cardiovascular y Metabolómica, Tecnologico de Monterrey, Monterrey, NL, Mexico.

Even though effective drugs for treating hypertension are available, a great percentage of patients have inadequate control of their blood pressure. Unwanted side effects and inappropriate oral drug adherence are important factors that contribute to the global problem of uncontrolled hypertension. Vaccination could provide a revolutionary therapy with long-lasting effects, increasing patient compliance and therefore better control of high blood pressure. Nowadays, current immunization approaches against hypertension target renin, angiotensin I, angiotensin II, and angiotensin II type 1 receptor, key elements of the renin-angiotensin system. This article reviews the different vaccination attempts with proteins and peptides against the different molecules of the renin-angiotensin system in the last two decades, safety issues, and other novel prospects biomarkers in hypertension, and summarizes the potential of this immunomodulatory approach in clinical practice.
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http://dx.doi.org/10.1007/s10741-020-10033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524378PMC
May 2021

Preoperative soluble VCAM-1 contributes to predict late mortality after coronary artery surgery.

Clin Cardiol 2020 Nov 8;43(11):1301-1307. Epub 2020 Aug 8.

Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile.

Background: Soluble vascular cell adhesion molecule-1 has been associated with long-term cardiovascular mortality in patients with stable coronary artery disease and to the development of new atrial fibrillation in subjects with cardiovascular risk factors but no evidence of cardiac disease.

Hypothesis: Preoperative soluble vascular cell adhesion molecule-1 predicts the risk of future all-cause death and cardiovascular death among patients submitted to elective coronary artery bypass surgery.

Methods: From a cohort of 312 patients who underwent elective coronary artery bypass surgery prospectively followed for a median of 6.7 years, we evaluated the prognostic role of preoperative soluble vascular cell adhesion molecule-1, inflammatory markers, CHA2DS2-VASc score and development of postoperative atrial fibrillation (POAF). Univariable and multivariable Cox regression analyses were performed to establish an association of these parameters with long term all-cause death and cardiovascular death.

Results: During 2112 person-years of follow-up, we observed 41 deaths, 10 were cardiovascular deaths. Independently increased levels of preoperative soluble vascular cell adhesion molecule-1, POAF, and CHA2DS2-VASc score were associated with all-cause mortality. After multivariate adjustment, elevated preoperative soluble vascular cell adhesion molecule-1 and POAF were the only independent predictors of all-cause death. Also, preoperative soluble vascular cell adhesion molecule-1, POAF, and CHA2DS2-VASc score resulted in being independent predictors of cardiovascular mortality.

Conclusions: Increased circulating levels of preoperative soluble vascular cell adhesion molecule-1, together with POAF and CHA2DS2-VASc score, were significantly associated with future all-cause death and cardiovascular death among patients submitted to coronary artery bypass surgery.
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http://dx.doi.org/10.1002/clc.23443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661653PMC
November 2020

Angiotensin-(1-9) prevents vascular remodeling by decreasing vascular smooth muscle cell dedifferentiation through a FoxO1-dependent mechanism.

Biochem Pharmacol 2020 10 5;180:114190. Epub 2020 Aug 5.

Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address:

The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1-9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1-9), with special focus on the control of vascular smooth muscle cell phenotype. Angiotensin-(1-9) decreased blood pressure and aorta media thickness in spontaneously hypertensive rats. Reduction of media thickness was associated with decreased vascular smooth muscle cell proliferation. In the A7r5 VSMC cell line and in primary cultures of rat aorta smooth muscle cells, angiotensin-(1-9) did not modify basal proliferation. However, angiotensin-(1-9) inhibited proliferation, migration and contractile protein decrease induced by platelet derived growth factor-BB. Moreover, angiotensin-(1-9) reduced Akt and FoxO1 phosphorylation at 30 min, followed by an increase of total FoxO1 protein content. Angiotensin-(1-9) effects were blocked by the AT2R antagonist PD123319, Akt-Myr overexpression and FoxO1 siRNA. These data suggest that angiotensin-(1-9) inhibits vascular smooth muscle cell dedifferentiation by an AT2R/Akt/FoxO1-dependent mechanism.
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http://dx.doi.org/10.1016/j.bcp.2020.114190DOI Listing
October 2020

β-Hydroxybutyrate Increases Exercise Capacity Associated with Changes in Mitochondrial Function in Skeletal Muscle.

Nutrients 2020 Jun 29;12(7). Epub 2020 Jun 29.

Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago 8380492, Chile.

β-hydroxybutyrate is the main ketone body generated by the liver under starvation. Under these conditions, it can sustain ATP levels by its oxidation in mitochondria. As mitochondria can modify its shape and function under different nutritional challenges, we study the chronic effects of β-hydroxybutyrate supplementation on mitochondrial morphology and function, and its relation to exercise capacity. Male C57BL/6 mice were supplemented with β-hydroxybutyrate mineral salt (3.2%) or control (CT, NaCl/KCl) for six weeks and submitted to a weekly exercise performance test. We found an increase in distance, maximal speed, and time to exhaustion at two weeks of supplementation. Fatty acid metabolism and OXPHOS subunit proteins declined at two weeks in soleus but not in tibialis anterior muscles. Oxygen consumption rate on permeabilized fibers indicated a decrease in the presence of pyruvate in the short-term treatment. Both the tibialis anterior and soleus showed decreased levels of Mitofusin 2, while electron microscopy assessment revealed a significant reduction in mitochondrial cristae shape in the tibialis anterior, while a reduction in the mitochondrial number was observed only in soleus. These results suggest that short, but not long-term, β‑hydroxybutyrate supplementation increases exercise capacity, associated with modifications in mitochondrial morphology and function in mouse skeletal muscle.
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http://dx.doi.org/10.3390/nu12071930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400376PMC
June 2020

PKD2/polycystin-2 induces autophagy by forming a complex with BECN1.

Autophagy 2021 07 30;17(7):1714-1728. Epub 2020 Jun 30.

Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile.

Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2, a Ca channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.
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http://dx.doi.org/10.1080/15548627.2020.1782035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354594PMC
July 2021

New emerging roles of Polycystin-2 in the regulation of autophagy.

Int Rev Cell Mol Biol 2020 11;354:165-186. Epub 2020 Mar 11.

Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile. Electronic address:

Polycystin-2 (PC2) is a calcium channel that can be found in the endoplasmic reticulum, the plasmatic membrane, and the primary cilium. The structure of PC2 is characterized by a highly ordered C-terminal tail with an EF-motif (calcium-binding domain) and a canonical coiled-coil domain (CCD; interaction domain), and its activity is regulated by interacting partners and post-translational modifications. Calcium mobilization into the cytosol by PC2 has been mainly associated with cell growth and differentiation, and therefore mutations or dysfunction of PC2 lead to renal and cardiac consequences. Interestingly, PC2-related pathologies are usually treated with rapamycin, an autophagy stimulator. Autophagy is an intracellular degradation process where recycling material is sequestered into autophagosomes and then hydrolyzed by fusion with a lysosome. Interestingly, several studies have provided evidence that PC2 may be required for autophagy, suggesting that PC2 maintains a physiologic catabolic state.
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http://dx.doi.org/10.1016/bs.ircmb.2020.02.006DOI Listing
December 2020

Inhibition of chymotrypsin-like activity of the proteasome by ixazomib prevents mitochondrial dysfunction during myocardial ischemia.

PLoS One 2020 26;15(5):e0233591. Epub 2020 May 26.

Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

The heart is critically dependent on mitochondrial respiration for energy supply. Ischemia decreases oxygen availability, with catastrophic consequences for cellular energy systems. After a few minutes of ischemia, the mitochondrial respiratory chain halts, ATP levels drop and ion gradients across cell membranes collapse. Activation of cellular proteases and generation of reactive oxygen species by mitochondria during ischemia alter mitochondrial membrane permeability, causing mitochondrial swelling and fragmentation and eventually cell death. The mitochondria, therefore, are important targets of cardioprotection against ischemic injury. We have previously shown that ixazomib (IXA), a proteasome inhibitor used for treating multiple myeloma, effectively reduced the size of the infarct produced by global ischemia in isolated rat hearts and prevented degradation of the sarcoplasmic reticulum calcium release channel RyR2. The aim of this work was to further characterize the protective effect of IXA by determining its effect on mitochondrial morphology and function after ischemia. We also quantified the effect of IXA on levels of mitofusin-2, a protein involved in maintaining mitochondrial morphology and mitochondria-SR communication. We found that mitochondria were significantly preserved and functional parameters such as oxygen consumption, the ability to generate a membrane potential, and glutathione content were improved in mitochondria isolated from hearts perfused with IXA prior to ischemia. IXA also blocked the release of cytochrome c observed in ischemia and significantly preserved mitofusin-2 integrity. These beneficial effects resulted in a significant decrease in the left ventricular end diastolic pressure upon reperfusion and a smaller infarct in isolated hearts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233591PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250417PMC
August 2020

FoxO1-Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth.

Nat Commun 2020 05 21;11(1):2551. Epub 2020 May 21.

Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, 75390-8573, USA.

Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1-Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1-Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1-Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.
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http://dx.doi.org/10.1038/s41467-020-16345-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242347PMC
May 2020
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