Recycle or die: The role of autophagy in cardioprotection

Abstract

Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggregates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy has an essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.

Introduction

Autophagy is an evolutionarily conserved process involved in the degradation of long-lived proteins and organelles. Cytoplasmic material is sequestered by an autophagosome and subsequently delivered to the lysosome where it is degraded by lysosomal proteases. There are three forms of autophagy; chaperone-mediated autophagy, microautophagy and macroautophagy. Macroautophagy is the most common form of autophagy in mammalian cells and will be herein referred to as autophagy. Autophagy occurs at low levels under normal conditions, but is also upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection [1], [2], [3], [4]. Autophagy can promote cell survival by generating free amino acids and fatty acids required to maintain function during nutrient-limiting conditions, or by removing damaged organelles and intracellular pathogens. However, autophagy might also promote cell death through excessive self-digestion and degradation of essential cellular constituents. Recent studies have also reported interactions between the autophagic and apoptotic pathways [5], [6].

Autophagy is an important process in the heart. It occurs at low basal levels under normal conditions and is important for the turnover of organelles [7]. Many studies have demonstrated that autophagy is upregulated in the heart in response to stress such as ischemia/reperfusion [4], [8], [9], [10], [11], [12]. Increased numbers of autophagosomes are a prominent feature in many cardiovascular diseases such as cardiac hypertrophy and heart failure [13], [14], [15], [16], [17], [18]. However, the functional role of the enhanced autophagy in the diseased heart is unclear and studies have yielded conflicting results regarding the role of autophagy in the heart. It is controversial whether the increased number of autophagosomes in dying cells contributes directly to cell death or represents an attempt to prevent it. In many studies, autophagic cell death has been defined by morphologic criteria and it has not been demonstrated that autophagy directly contributed to cell death. However, recent genetic studies disrupting the autophagic pathway have yielded increasing insight into the role of autophagy in cell survival and death in the heart. In this review, we discuss the emerging evidence that autophagy has a dual role in the heart where it can protect against or contribute to cell death depending on the stimulus.