Autophagy in cardiovascular health and disease

doi:10.1016/bs.pmbts.2020.04.022

Progress in Molecular Biology and Translational Science

Volume 172, 2020, Pages 87-106

https://doi.org/10.1016/bs.pmbts.2020.04.022 Get rights and content

Abstract

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.

Introduction

Macroautophagy (herein referred to as autophagy) is a homeostatic and survival mechanism required for quality control in almost all eukaryotic cells, including those comprising the cardiovascular system.¹ In particular, long-lived cardiac myocytes critically depend on the housekeeping function of autophagy as they are terminally-differentiated cells.² Therefore, the heart, and subsequently the whole circulatory system, is particularly vulnerable to autophagic perturbations. In this chapter, we focus on available evidence that shaped the current understanding of the role of autophagy in cardiovascular health maintenance, and discuss how autophagy can be exploited to counteract pertinent cardiovascular diseases.

Section snippets

Autophagy in cardiovascular health

The fundamental role of autophagy in cardiovascular health can be easily inferred from the consequences of modifying its activity in cardiac or vascular cell types. In this regard, several experimental studies employed genetic, dietary and pharmacological interventions to activate or attenuate autophagy, showing that compromised autophagy causes a significant deterioration in cardiovascular health; meanwhile its activation coincides with improved cardiac and vascular functions.

Autophagy in cardiovascular disease

Recent years have witnessed an ample number of experimental studies demonstrating that repeated or continuous stimulation of autophagy could be also beneficial against specific cardiovascular diseases.³⁹ To this end, we will present currently prevailing views and highlight recent advances in understanding the involvement of autophagy in a subset of common and life-threatening cardiovascular disorders.

Concluding remarks

Any perturbations in autophagy that affect the formation of autophagosomes or their subsequent degradation by lysosomes lead to impaired function and homeostasis of long-lived cardiomyocytes and other cells in the cardiovascular system. Hence, the cytoprotective function of autophagy is essential to sustain cardiovascular health and protect from disease (Fig. 1). With that in mind, future experimental studies will need to determine the long-term impact, including the benefits and potential side

Acknowledgments

The authors are grateful to support from the Austrian Science Fund FWF (grants I3301 ERA-CVD [MINOTAUR] to S.S.; V530 to S.L.H.; SFB LIPOTOX F3007 & F3012, W1226, P29203, P29262, P27893, P31727 to F.M.), the Austrian Society of Cardiology, (to M.A.), the European Society of Cardiology (to M.A.), the Austrian Federal Ministry of Education, Science and Research (to F.M.), and the BioTechMed Graz (to F.M., S.L.H. and S.S).

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Chapter Six - Autophagy in cardiovascular health and disease

Abstract

Introduction

Section snippets

Autophagy in cardiovascular health

Autophagy in cardiovascular disease

Concluding remarks

Acknowledgments

Cell

J Mol Cell Cardiol

Biochim Biophys Acta

Mech Ageing Dev

Cell Metab

Cell Metab

Atherosclerosis

J Am Coll Cardiol

J Biol Chem

Cell

Int J Cardiol

J Biol Chem

Biochem Pharmacol

Biochem Pharmacol

J Mol Cell Cardiol

J Mol Cell Cardiol

Evidence for cardiomyocyte renewal in humans

Science

Autophagy in mammalian development and differentiation

Nat Cell Biol

Inhibition of autophagy in the heart induces age-related cardiomyopathy

Autophagy

Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice

Nature

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Autophagy

Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease)

Nature

Defective autophagy in vascular smooth muscle cells alters contractility and Ca(2)(+) homeostasis in mice

Am J Physiol Heart Circ Physiol

Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor

Nat Med

Autophagy is essential for cardiac morphogenesis during vertebrate development

Autophagy

GSK-3alpha is a central regulator of age-related pathologies in mice

J Clin Invest

mTOR hyperactivation by ablation of tuberous sclerosis complex 2 in the mouse heart induces cardiac dysfunction with the increased number of small mitochondria mediated through the down-regulation of autophagy

PLoS One

A conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction

Nat Commun

Deletion of PRKAA triggers mitochondrial fission by inhibiting the autophagy-dependent degradation of DNM1L

Autophagy

Autophagy in cardiovascular aging

Circ Res

Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice

Circulation

Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1-mediated autophagy regulation

Aging Cell

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart

Nat Commun

Opposing effects on cardiac function by calorie restriction in different-aged mice

Aging Cell

Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice

Aging Cell

Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart

Aging Cell

Calorie restriction can reverse, as well as prevent, aging cardiomyopathy

Age (Dordr)

Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress

Aging Cell

Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans

Cell Metab

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Autophagy