Publications by authors named "Mahmoud Abdellatif"

27 Publications

  • Page 1 of 1

Exercise-induced sudden cardiac death is caused by mitochondrio-nuclear translocation of AIF.

Cell Death Dis 2021 04 9;12(4):383. Epub 2021 Apr 9.

Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, 94805, France.

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http://dx.doi.org/10.1038/s41419-021-03677-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035199PMC
April 2021

Targeting the Mitochondria-Proteostasis Axis to Delay Aging.

Front Cell Dev Biol 2021 11;9:656201. Epub 2021 Mar 11.

Department of Cardiology, Medical University of Graz, Graz, Austria.

Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.
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http://dx.doi.org/10.3389/fcell.2021.656201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991595PMC
March 2021

Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling.

Cardiovasc Res 2021 Mar 22. Epub 2021 Mar 22.

Department of Cardiology, Medical University of Graz, Graz, Austria.

Aims: Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.

Methods And Results: RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.

Conclusion: Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.
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http://dx.doi.org/10.1093/cvr/cvab112DOI Listing
March 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

Circulatory miR-221 & miR-542 expression profiles as potential molecular biomarkers in Hepatitis C Virus mediated liver cirrhosis and hepatocellular carcinoma.

Virus Res 2021 Apr 16;296:198341. Epub 2021 Feb 16.

Biochemistry & Molecular Biology Department, Faculty of Pharmacy, The British University in Egypt (BUE), Suez Rd, El Sherouk City, Cairo Governorate, 11837 Egypt. Electronic address:

Chronic hepatitis C virus (cHCV) is a leading cause for liver cirrhosis (LC) and hepatocellular carcinoma (HCC) globally. So far, there is no optimal non-invasive biomarker for diagnosing HCV associated hepatic disorders. Circulatory miRNAs have drawn great attention as potential non-invasive biomarkers in various diseases. We quantified miR-221 and miR-542 levels in the plasma of 153 Egyptian patients (38 healthy controls (HC), 36 cHCV, 39 HCV-LC and 40 HCV mediated HCC groups) using qRT-PCR. All diseased groups exhibited significant upregulation in miR-221 expression (P < 0.001) with an increasing trend towards late stages (HCV-LC+HCV-HCC) as compared to early stages (cHCV). MiR-221 could significantly discriminate HCC patients from cHCV and HCV-LC with (AUC=0.698; P = 0.002) and (AUC=0.644; P = 0.032) respectively. Furthermore, miR-221 could significantly discriminate between HCC and non-HCC groups (AUC=0.670, P<0.001). HCV-LC & cHCV groups showed significant upregulation in miR-542 with remarkable downregulation in HCC group (P = 0.004). MiR-542 exhibited diagnostic power of (AUC=0.640; P = 0.044) and (AUC= 0.644; P = 0.040) for discriminating HCV-LC from HCC and cHCV groups respectively. Both miR-221 and miR-542 were significantly upregulated in cirrhotic group (HCV-LC) (P = 0.046 and P = 0.002 respectively) as compared to non-cirrhotic group (cHCV+HC). Combining both miRNAs in a panel significantly improved diagnostic performance as follows; HC and HCC (AUC=0.714, P < 0.001); HCC and LC (AUC=0.714, P = 0.001); HC and LC (AUC=0.710, P = 0.002) and also cHCV and HCC (AUC=0.672, P = 0.006). In conclusion, both miR-221 & miR-542 could stand as a standalone biomarker for staging various HCV associated disorders. Combining them would greatly enhance their diagnostic potential.
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http://dx.doi.org/10.1016/j.virusres.2021.198341DOI Listing
April 2021

Nicotinamide for the treatment of heart failure with preserved ejection fraction.

Sci Transl Med 2021 Feb;13(580)

Department of Cardiology, Medical University of Graz, Graz 8036, Austria.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD). Elevating NAD by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.
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http://dx.doi.org/10.1126/scitranslmed.abd7064DOI Listing
February 2021

Co-ordinated mitochondrial degradation by autophagy and heterophagy in cardiac homeostasis.

Cardiovasc Res 2021 01;117(1):e1-e3

Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.

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http://dx.doi.org/10.1093/cvr/cvaa345DOI Listing
January 2021

Scientists on the Spot: from the Scientists of Tomorrow to the scientist of today.

Cardiovasc Res 2020 11;116(13):e184-e185

Cardiovascular Program-ICCC, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain.

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http://dx.doi.org/10.1093/cvr/cvaa277DOI Listing
November 2020

CaMKIIδC Drives Early Adaptive Ca Change and Late Eccentric Cardiac Hypertrophy.

Circ Res 2020 10 21;127(9):1159-1178. Epub 2020 Aug 21.

Department of Pharmacology, University of California, Davis, CA (S.L.-H., A.W.H., S.M., B.M.W., J.B., D.M.B.).

Rationale: CaMKII (Ca-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca handling and CaMKII activation in hypertrophy and HF.

Objective: To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice.

Methods And Results: We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca content, Ca transient amplitude, and [Ca] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca transient effects reversed, but further increases in nuclear and time-averaged [Ca] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions.

Conclusions: We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca-CaMKIIδC axis contributes to eccentric hypertrophy and HF.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547876PMC
October 2020

Autophagy in cardiovascular health and disease.

Prog Mol Biol Transl Sci 2020 12;172:87-106. Epub 2020 May 12.

Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia. Electronic address:

Autophagy is a cellular housekeeping and quality control mechanism that is essential for homeostasis and survival. By virtue of this role, any perturbations to the flow of this process in cardiac or vascular cells can elicit harmful effects on the cardiovascular system, and subsequently affect whole organismal health. In this chapter, we summarize the preclinical evidence supporting the role of autophagy in sustaining cardiovascular health during homeostasis and disease. Furthermore, we discuss how autophagy activation by dietary, genetic and pharmaceutical interventions can be exploited to counteract common cardiovascular disorders, including atherosclerosis, coronary artery disease, diabetic cardiomyopathy, arrhythmia, chemotherapy-induced cardiotoxicity and heart failure.
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http://dx.doi.org/10.1016/bs.pmbts.2020.04.022DOI Listing
June 2021

Immunometabolism: a key target to improve microcirculation in ageing.

Cardiovasc Res 2020 04;116(5):e48-e50

Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.

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http://dx.doi.org/10.1093/cvr/cvaa060DOI Listing
April 2020

Cardiovascular benefits of intermittent fasting.

Cardiovasc Res 2020 03;116(3):e36-e38

Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.

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http://dx.doi.org/10.1093/cvr/cvaa022DOI Listing
March 2020

-acetylaspartate availability is essential for juvenile survival on fat-free diet and determines metabolic health.

FASEB J 2019 12 1;33(12):13808-13824. Epub 2019 Nov 1.

Institute of Biochemistry, Graz University of Technology, Graz, Austria.

-acetylaspartate (NAA) is synthesized by aspartate -acetyltransferase (gene: ) from acetyl-coenzyme A and aspartate. In the brain, NAA is considered an important energy metabolite for lipid synthesis. However, the role of NAA in peripheral tissues remained elusive. Therefore, we characterized the metabolic phenotype of knockout (ko) and adipose tissue-specific (ako) -ko mice as well as NAA-supplemented mice on various diets. We identified an important role of NAA availability in the brain during adolescence, as 75% of -ko mice died on fat-free diet (FFD) after weaning but could be rescued by NAA supplementation. In adult life, NAA deficiency promotes a beneficial metabolic phenotype, as -ko and -ako mice showed reduced body weight, increased energy expenditure, and improved glucose tolerance on chow, high-fat, and FFDs. Furthermore, -deficient adipocytes exhibited increased mitochondrial respiration, ATP synthesis, and an induction of browning. Conversely, NAA-treated wild-type mice showed reduced adipocyte respiration and lipolysis and increased lipogenesis, culminating in reduced energy expenditure, glucose tolerance, and insulin sensitivity. Mechanistically, our data point to a possible role of NAA as modulator of pancreatic insulin secretion and suggest NAA as a critical energy metabolite for adipocyte and whole-body energy homeostasis.-Hofer, D. C., Zirkovits, G., Pelzmann, H. J., Huber, K., Pessentheiner, A. R., Xia, W., Uno, K., Miyazaki, T., Kon, K., Tsuneki, H., Pendl, T., Al Zoughbi, W., Madreiter-Sokolowski, C. T., Trausinger, G., Abdellatif, M., Schoiswohl, G., Schreiber, R., Eisenberg, T., Magnes, C., Sedej, S., Eckhardt, M., Sasahara, M., Sasaoka, T., Nitta, A., Hoefler, G., Graier, W. F., Kratky, D., Auwerx, J., Bogner-Strauss, J. G. -acetylaspartate availability is essential for juvenile survival on fat-free diet and determines metabolic health.
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http://dx.doi.org/10.1096/fj.201801323RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894082PMC
December 2019

Highlights of ESC Congress 2019: a report from the ESC Scientists of Tomorrow.

Cardiovasc Res 2019 Nov;115(13):e151-e154

Cardiovascular Cell Biology, Department of Cell and Chemical Biology, Postzone S-1-P, Leiden University Medical Center, RC, Leiden, The Netherlands.

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http://dx.doi.org/10.1093/cvr/cvz266DOI Listing
November 2019

Autophagy promotes longevity-except in the presence of 'leaky' mitochondria.

Cardiovasc Res 2019 10;115(12):e118-e120

Department of Cardiology, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1093/cvr/cvz224DOI Listing
October 2019

Corrigendum to "Cardioprotection by spermidine does not depend on structural characteristics of the myocardial microcirculation in aged mice" [Exp Gerontol 199 (2019) 82-88].

Exp Gerontol 2019 Jul;122:139

Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.exger.2019.05.009DOI Listing
July 2019

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species.

Nat Commun 2019 02 19;10(1):651. Epub 2019 Feb 19.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
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http://dx.doi.org/10.1038/s41467-019-08555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180PMC
February 2019

Cardioprotection by spermidine does not depend on structural characteristics of the myocardial microcirculation in aged mice.

Exp Gerontol 2019 05 28;119:82-88. Epub 2019 Jan 28.

Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany. Electronic address:

Aims: Ageing is associated with cardiovascular disease and reduced cardiac function. This cardiac functional decline is accompanied by cardiac remodeling and alterations in cardiomyocyte composition. Recently, it was shown that the natural polyamine spermidine preserves cardiac function and cardiomyocyte composition in old mice. As cardiac function critically relies on blood supply, we tested whether spermidine has also beneficial effects on ageing-associated changes of the myocardial microcirculation.

Methods: Using transmission electron microscopy, the left ventricular capillaries of young (4-months old) and aged (24-months old) C57BL/6J male mice were investigated by stereology. Aged mice were subdivided into an untreated group and a group that was fed spermidine late in life for 6 months. Specifically, total volume, surface area and length of capillaries as well as endothelial thickness were estimated. Additionally, the total length of precapillary arterioles was assessed. The protein level of VEGF-A was measured using Western blot.

Results: Ageing was associated with whole heart and left ventricular hypertrophy. All total capillary-related values (including volume, surface area and length) were significantly higher in 24-month-old mice compared with 4-month-old mice. Moreover, VEGF-A expression was significantly enhanced in aged mice. The mean thickness of the endothelium was not different, but the mean area of myocardium supplied by capillaries was smaller in old mice. Spermidine treatment had no significant effect on the ageing-associated structural changes or VEGF-A expression.

Conclusions: In conclusion, in the left ventricles of aged mice the growth of capillaries and arterioles supplying cardiomyocytes were in proportion to whole organ hypertrophy. Spermidine had no effect on quantitative characteristics of capillaries or arterioles, suggesting that the beneficial effects of spermidine on the ageing heart do not depend on the quantitative structural characteristics of the microcirculation which does not exclude potential functional differences between the groups.
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http://dx.doi.org/10.1016/j.exger.2019.01.026DOI Listing
May 2019

Cardioprotective effects of autophagy induction in sepsis.

Ann Transl Med 2018 Nov;6(Suppl 1):S61

Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.

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http://dx.doi.org/10.21037/atm.2018.10.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291539PMC
November 2018

Autophagy in Cardiovascular Aging.

Circ Res 2018 09;123(7):803-824

Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France (G.K.).

Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312208DOI Listing
September 2018

Cold-Induced Thermogenesis Depends on ATGL-Mediated Lipolysis in Cardiac Muscle, but Not Brown Adipose Tissue.

Cell Metab 2017 Nov 5;26(5):753-763.e7. Epub 2017 Oct 5.

Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria. Electronic address:

Fatty acids (FAs) activate and fuel UCP1-mediated non-shivering thermogenesis (NST) in brown adipose tissue (BAT). Release of FAs from intracellular fat stores by adipose triglyceride lipase (ATGL) is considered a key step in NST. Accordingly, the severe cold intolerance of global ATGL knockout (AKO) mice has been attributed to defective BAT lipolysis. Here we show that this conclusion is incorrect. We demonstrate that although the BAT-specific loss of ATGL impairs BAT lipolysis and alters BAT morphology, it does not compromise the β-adrenergic thermogenic response or cold-induced NST. Instead, NST depends on nutrient supply or lipolysis in white adipose tissue during fasting, suggesting that circulating energy substrates are sufficient to fuel NST. Cold intolerance in AKO mice is not caused by BAT dysfunction as previously suspected but by severe cardiomyopathy. We conclude that functional NST requires adequate substrate supply and cardiac function, but does not depend on ATGL-mediated lipolysis in BAT.
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http://dx.doi.org/10.1016/j.cmet.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683855PMC
November 2017

Dietary spermidine for lowering high blood pressure.

Autophagy 2017 Apr 24;13(4):767-769. Epub 2017 Jan 24.

a Institute of Molecular Biosciences, NAWI Graz, University of Graz , Graz , Austria.

Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure. The high blood pressure-lowering effect likely results from improved global arginine bioavailability and protection from hypertension-associated renal damage. The polyamine spermidine is naturally present in human diets, though to a varying amount depending on food type and preparation. In humans, high dietary spermidine intake correlates with reduced blood pressure and decreased risk of cardiovascular disease and related death. Altogether, spermidine represents a cardio- and vascular-protective autophagy inducer that can be readily integrated in common diets.
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http://dx.doi.org/10.1080/15548627.2017.1280225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381711PMC
April 2017

Cardioprotection and lifespan extension by the natural polyamine spermidine.

Nat Med 2016 12 14;22(12):1428-1438. Epub 2016 Nov 14.

Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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http://dx.doi.org/10.1038/nm.4222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806691PMC
December 2016

Right ventricular end-diastolic stiffness heralds right ventricular failure in monocrotaline-induced pulmonary hypertension.

Am J Physiol Heart Circ Physiol 2016 10 29;311(4):H1004-H1013. Epub 2016 Jul 29.

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anesthesiology, Hospital São João, Porto, Portugal

Recent studies suggest right ventricular (RV) stiffness is important in pulmonary hypertension (PH) prognosis. Smaller stroke volume (SV) variation after a certain RV end-diastolic pressure (EDP) respiratory variation as assessed by spectral transfer function (STF) may identify RV stiffness. Our aim was to evaluate RV stiffness in monocrotaline (MCT)-induced PH progression and to validate STF gain between EDP and SV as marker of stiffness. Seven-week-old male Wistar rats randomly injected with 60 mg/kg MCT or vehicle were divided into three groups (n = 12 each) according to cardiac index (CI): controls (Ctrl), preserved CI (MCT pCI), and reduced CI (MCT rCI). All underwent RV pressure-volume (PV) evaluation 24-34 days after MCT, under halogenate anesthesia and constant positive-pressure ventilation. End-diastolic stiffness (β), end-systolic elastance (Ees), arterial elastance for indexed volumes (Ea), and preload recruitable stroke work (PRSW) were obtained and beat-to-beat fluctuations during ventilation assessed by STF. Ea was the strongest determinant of CI, alongside β but not PRSW. MCT rCI showed impaired ventricular-vascular coupling (VVC) and higher β, along with low end-diastolic pressure (EDP) and stroke volume index (SV) STF gain, denoting impaired preload reserve. On multivariate analysis β and not Ees correlated with EDP-SV STF gain (P < 0.001). Receiver-operating characteristics (ROC) curve analysis of EDP-SV STF gain showed an area under curve of 0.84 for β prediction (P = 0.002). Afterload, impaired VVC and RV stiffness are major players in RV failure. RV stiffness can be assessed by STF gain analysis of respiratory fluctuations between EDP and SV, which may constitute a prognostic tool in PH.
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http://dx.doi.org/10.1152/ajpheart.00202.2016DOI Listing
October 2016

Spectral transfer function analysis of respiratory hemodynamic fluctuations predicts end-diastolic stiffness in preserved ejection fraction heart failure.

Am J Physiol Heart Circ Physiol 2016 Jan 16;310(1):H4-13. Epub 2015 Oct 16.

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anesthesiology, Hospital São João, Porto, Portugal

Preserved ejection fraction heart failure (HFpEF) diagnosis remains controversial, and invasive left ventricular (LV) hemodynamic evaluation and/or exercise testing is advocated by many. The stiffer HFpEF myocardium may show impaired stroke volume (SV) variation induced by fluctuating LV filling pressure during ventilation. Our aim was to investigate spectral transfer function (STF) gain from end-diastolic pressure (EDP) to indexed SV (SVi) in experimental HFpEF. Eighteen-week-old Wistar-Kyoto (WKY) and ZSF1 lean (ZSF1 Ln) and obese rats (ZSF1 Ob) randomly underwent LV open-chest (OC, n = 8 each group) or closed-chest hemodynamic evaluation (CC, n = 6 each group) under halogenate anesthesia and positive-pressure ventilation at constant inspiratory pressure. Beat-to-beat fluctuations in hemodynamic parameters during ventilation were assessed by STF. End-diastolic stiffness (βi) and end-systolic elastance (Eesi) for indexed volumes were obtained by inferior vena cava occlusion in OC (multibeat) or single-beat method estimates in CC. ZSF1 Ob showed higher EDP spectrum (P < 0.001), higher STF gain between end-diastolic volume and EDP, and impaired STF gain between EDP and SVi compared with both hypertensive ZSF1 Ln and normotensive WKY controls (P < 0.001). Likewise βi was only higher in ZSF1 Ob while Eesi was raised in both ZSF1 groups. On multivariate analysis βi and not Eesi correlated with impaired STF gain from EDP to SVi (P < 0.001), and receiver-operating characteristics analysis showed an area under curve of 0.89 for higher βi prediction (P < 0.001). Results support further clinical testing of STF analysis from right heart catheterization-derived EDP surrogates to noninvasively determined SV as screening/diagnostic tool to assess myocardial stiffness in HFpEF.
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http://dx.doi.org/10.1152/ajpheart.00399.2015DOI Listing
January 2016

Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction.

Am J Physiol Heart Circ Physiol 2015 Nov 25;309(10):H1648-54. Epub 2015 Sep 25.

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anesthesiology, Hospital São João, Porto, Portugal

Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant β, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (τ), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 × monoexponentially derived τ (τexp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF.
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http://dx.doi.org/10.1152/ajpheart.00397.2015DOI Listing
November 2015

Echocardiography and invasive hemodynamics during stress testing for diagnosis of heart failure with preserved ejection fraction: an experimental study.

Am J Physiol Heart Circ Physiol 2015 Jun 10;308(12):H1556-63. Epub 2015 Apr 10.

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anesthesiology, Hospital São João, Porto, Portugal

Inclusion of exercise testing in diagnostic guidelines for heart failure with preserved ejection fraction (HFpEF) has been advocated, but the target population, technical challenges, and underlying pathophysiological complexity raise difficulties to implementation. Hemodynamic stress tests may be feasible alternatives. Our aim was to test Trendelenburg positioning, phenylephrine, and dobutamine in the ZSF1 obese rat model to find echocardiographic surrogates for end-diastolic pressure (EDP) elevation and HFpEF. Seventeen-week-old Wistar-Kyoto, ZSF1 lean, and obese rats (n = 7 each) randomly and sequentially underwent (crossover) Trendelenburg (30°), 5 μg·Kg(-1)·min(-1) dobutamine, and 7.5 μg·Kg(-1)·min(-1) phenylephrine with simultaneous left ventricular (LV) pressure-volume loop and echocardiography evaluation under halogenate anesthesia. Effort testing with maximum O2 consumption (V̇o 2 max) determination was performed 1 wk later. Obese ZSF1 showed lower effort tolerance and V̇o 2 max along with higher resting EDP. Both Trendelenburg and phenylephrine increased EDP, whereas dobutamine decreased it. Significant correlations were found between EDP and 1) peak early filling Doppler velocity of transmitral flow (E) to corresponding myocardial tissue Doppler velocity (E') ratio, 2) E to E-wave deceleration time (E/DT) ratio, and 3) left atrial area (LAA). Diagnostic efficiency of E/DT*LAA by receiver-operating characteristic curve analysis for elevation of EDP above a cut-off of 13 mmHg during hemodynamic stress was high (area under curve, AUC = 0.95) but not higher than that of E/E' (AUC = 0.77, P = 0.15). Results in ZSF1 obese rats suggest that noninvasive echocardiography after hemodynamic stress induced by phenylephrine or Trendelenburg can enhance diagnosis of stable HFpEF and constitute an alternative to effort testing.
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http://dx.doi.org/10.1152/ajpheart.00076.2015DOI Listing
June 2015