Review Article
Autophagy as a therapeutic target in cardiovascular disease

https://doi.org/10.1016/j.yjmcc.2011.06.010Get rights and content

Abstract

The epidemic of heart failure continues apace, and development of novel therapies with clinical efficacy has lagged. Now, important insights into the molecular circuitry of cardiovascular autophagy have raised the prospect that this cellular pathway of protein quality control may be a target of clinical relevance. Whereas basal levels of autophagy are required for cell survival, excessive levels – or perhaps distinct forms of autophagic flux – contribute to disease pathogenesis. Our challenge will be to distinguish mechanisms that drive adaptive versus maladaptive autophagy and to manipulate those pathways for therapeutic gain. Recent evidence suggests this may be possible. Here, we review the fundamental biology of autophagy and its role in a variety of forms of cardiovascular disease. We discuss ways in which this evolutionarily conserved catabolic mechanism can be manipulated, discuss studies presently underway in heart disease, and provide our perspective on where this exciting field may lead in the future. This article is part of a special issue entitled ‘‘Key Signaling Molecules in Hypertrophy and Heart Failure.’’

Highlights

► Discussion of the role of cardiomyocyte autophagy in cardiac plasticity and disease. ► Therapeutic manipulation of autophagic pathways and governing signaling cascades. ► Autophagy-related patents and putative applications in cardiovascular disease.

Introduction

According to World Health Organization estimates, cardiovascular diseases are the number one cause of death globally [1], a sad ranking which is expected to persist into the future. Costs deriving from cardiovascular disease morbidity and mortality are staggering, estimated to exceed $500 billion in the US alone [1]. In light of these sobering facts, there is urgent need to identify novel mechanisms of disease pathogenesis and therapeutic targets capable of stemming inexorable progression of disease.

For three decades, it has been recognized that lysosomal pathways of protein degradation are prevalent in most forms of heart disease [2]. Until recently, however, it has been difficult to discern the role(s) of these catabolic pathways: whether they promote or antagonize disease pathogenesis. Now, based on molecular discoveries in yeast, a model has emerged of an intricate cascade of events leading to cargo sequestration and delivery to lysosomes. This process, termed autophagy, is an evolutionarily conserved mechanism of protein and organelle catabolism present within all eukaryotic cells [3], [4]. To date, 32 autophagy-related (ATG) genes have been identified which regulate autophagosome processing, including a subset termed the “core autophagy machinery” essential for autophagosome formation [5]. Now, armed with specifics regarding the molecular anatomy of the autophagic machinery, it is becoming possible to determine the role(s) of autophagy in numerous pathological processes [6], including cardiovascular disease [7], [8].

Section snippets

Autophagy, cellular cannibalization

Autophagy is a catabolic process whereby cells respond to energy stress by recycling intracellular components: proteins, ribosomes, lipids, and even entire organelles. [9]. In the presence of ample nutrient supply, anabolic reactions predominate within the cell, and autophagy is maintained at low levels critical for normal cellular homeostasis and survival [10], [11]. For example, basal levels of autophagic flux are required to degrade long-lived proteins, lipid droplets, and dysfunctional

Molecular anatomy of autophagy

In overview, autophagy is a mechanism whereby cytoplasmic components are sequestered in a double-membrane vesicle (autophagosome) for delivery to the lysosome for breakdown [17]. However, the details of the process itself are quite intricate, involving membrane dynamics, vesicle trafficking, and cargo degradation. The autophagic cascade has been divided into distinct stages, viz. induction, cargo recognition and selection, vesicle formation, autophagosome-vacuole fusion, cargo breakdown and

mTORC1

A central nexus of autophagy control is mTOR, a protein kinase that regulates cell growth and metabolism in response to nutrients, growth factors, ATP, and stress [31] (Fig. 2). mTOR exists as two distinct multiprotein complexes, TORC1 and TORC2. TORC1 (comprising mTOR, Raptor, and mLST8) is rapamycin sensitive and mediates the temporal control of cell growth by transcription, translation, and autophagy. TORC2 (formed by mTOR, Rictor, mLST8, and Protor) is rapamycin insensitive and governs

Autophagy in cardiovascular biology

Activation of autophagic flux pathways occurs across a spectrum. At one end, low-level constitutive autophagic flux is fundamental to cell survival. At the other end of the spectrum, over-active autophagy can deplete a cell of elements required for life, thereby triggering cell death. In between these two extremes, the actions of autophagy are complex and potentially pro- or anti-survival (Fig. 3).

Cardiac autophagy as a therapeutic target

Despite significant advances in cardiovascular therapeutics, both pharmacologic and device-based, the incidence of heart failure remains distressingly high [1]. A significant reason for this apparent failure is the fact that our understanding of cardiac plasticity and pathological remodeling is incomplete [86]. Recent scientific advances, however, have raised the tantalizing prospect of targeting the myocyte autophagic reaction as a novel means of achieving therapeutic gain.

In the setting of

Future of cardiovascular autophagy research

As noted, recent findings by our group demonstrate that, at least in the context of cardiac hypertrophy, HDACi blocks pathological cardiomyocyte autophagy and blunts hypertrophic growth [59]. Given the ever-expanding burden of cardiac pathology worldwide, these findings merit further study in patients with heart disease.

Two HDAC inhibitors, Zolinza® (vorinostat) (a hydroxamic acid derivative structurally related to TSA) and romidepsin (Istoda®) have been granted FDA approval for the treatment

Concluding remarks

Autophagic “self-eating” is a critical pro-survival response in cardiomyocytes exposed to diverse forms of pathological insult. In this light, the growing number of cardioprotective therapies affecting autophagic activity is encouraging. For example, a recent report showed that chloramphenicol succinate activates autophagy in I/R-stressed swine heart, and this therapy was associated with benefit [99]. Looking to the future, it is possible to envision harnessing therapeutic agents already in

Disclosure statement

None.

Acknowledgments

This work was supported by grants from the NIH (HL-075173, JAH; HL-080144, JAH; HL-090842, JAH), AHA (0640084N, JAH), ADA (7-08-MN-21-ADA, JAH), the AHA-Jon Holden DeHaan Foundation (0970518N, JAH), and the Fondo Nacional de Desarrollo Cientifico y Tecnologico, Chile (FONDECYT 1080436, SL; FONDAP 15010006, SL). SL is on a sabbatical leave at the University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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