Myocardial stress and autophagy: mechanisms and potential therapies

Key Points Autophagic breakdown of cellular components is regulated by multiple signalling networks, including insulin and 5′-AMP-activated protein kinase pathways, and is essential for cardiomyocyte survival in response to stress A new understanding of cargo-selective autophagy in the heart is emerging, relating to specific pathways for degradation of proteins (macrophagy), mitochondria (mitophagy), and glycogen (glycophagy) Disturbances in cardiomyocyte autophagy are evident in numerous cardiac pathologies, including cardiac hypertrophy, pressure-overload heart failure, ischaemic heart disease, as well as diabetic and age-related cardiomyopathies The cardioprotective effects of autophagy in acute energy stress are clear, but whether sustained elevation of autophagy in chronic disease states is beneficial or detrimental is not known Autophagy is a potentially attractive therapeutic target in cardiopathology; several new areas for investigation related to therapies for cardiomyocyte-specific and cargo-specific autophagy have been identified Autophagy is a ubiquitous cellular catabolic process responsive to energy stress. Activation of autophagy is cardioprotective in some settings (ischaemia and ischaemic preconditioning), but sustained autophagy has been linked with cardiopathology in other settings (prolonged pressure overload and heart failure). In this Review, induction of autophagy associated with cardiac benefit or detriment is considered, and prospects for pharmacological intervention are discussed. Autophagy is a ubiquitous cellular catabolic process responsive to energy stress. Research over the past decade has revealed that cardiomyocyte autophagy is a prominent homeostatic pathway, important in adaptation to altered myocardial metabolic demand. The cellular machinery of autophagy involves targeted direction of macromolecules and organelles for lysosomal degradation. Activation of autophagy has been identified as cardioprotective in some settings (that is, ischaemia and ischaemic preconditioning). In other situations, sustained autophagy has been linked with cardiopathology (for example, sustained pressure overload and heart failure). Perturbation of autophagy in diabetic cardiomyopathy has also been observed and is associated with both adaptive and maladaptive responses to stress. Emerging research findings indicate that various forms of selective autophagy operate in parallel to manage various types of catabolic cellular cargo including mitocho