Autophagy in load-induced heart disease

Abstract

The heart is a highly plastic organ capable of remodeling in response to changes in physiological or pathological demand. For example, when workload increases, compensatory hypertrophic growth of individual cardiomyocytes occurs to increase cardiac output. Sustained stress, however, such as that occurring with hypertension or following myocardial infarction, triggers changes in energy metabolism and sarcomeric protein composition, loss of cardiomyocytes, ventricular dilation, reduced pump function, and ultimately heart failure. It has been known for some time that autophagy is active in cardiomyocytes, occurring at increased levels in disease. Now, with recent advances in our understanding of molecular mechanisms governing autophagy, the potential contributions of cardiomyocyte autophagy to ventricular remodeling and disease pathogenesis are being explored. As part of this work, several recent studies have focused on autophagy in heart disease elicited by changes in hemodynamic load. Pressure overload stress elicits a robust autophagic response in cardiomyocytes that is maladaptive, contributing to disease progression. In this context, load-induced aggregation of intracellular proteins is a proximal event triggering autophagic clearance mechanisms. These findings in the setting of pressure overload contrast with protein aggregation occurring in a model of protein chaperone malfunction, where activation of autophagy is beneficial, antagonizing disease progression. Here, we review recent studies of cardiomyocyte autophagy in load-induced disease and address molecular mechanisms and unanswered questions.

Figure 1

Working model of the dual nature of autophagy in heart disease. Basal activation of autophagy is required for normal cellular function. Too little or too much autophagy can each be maladaptive. Hemodynamic stress triggers autophagy, which, depending on the amplitude and duration of autophagic activation and the initial level of basal autophagic flux, may elicit either harmful or beneficial effects.

Figure 2

Working model of autophagic activation in load-induced heart disease. Hemo-dynamic stress triggers an autophagic response via multiple mechanisms, including protein damage/aggregation, ROS accumulation, Ca²⁺ overload, and nutrient deprivation. Downstream interplay among these pathways elicits an autophagic response. Opening of the mitochondrial permeability transition pore may elicit selective targeting of damaged mitochondria. In parallel, misfolded proteins are degraded by the ubiquitin– proteasome system, as well as sequestered into aggregates and aggresomes.