Role of autophagy in heart failure associated with aging

Abstract

Heart failure is a progressive disease, leading to reduced quality of life and premature death. Adverse ventricular remodeling involves changes in the balance between cardiomyocyte protein synthesis and degradation, forcing these myocytes in equilibrium between life and death. In this context, autophagy has been recognized to play a role in the pathophysiology of heart failure. At basal levels, autophagy performs housekeeping functions, maintaining cardiomyocyte function and ventricular mass. Autophagy also occurs in the failing human heart, and upregulation has been reported in animal models of pressure overload-induced heart failure. Although the factors that determine whether autophagy will be protective or detrimental are not well known, the level and duration of autophagy seem important. Autophagy may antagonize ventricular hypertrophy by increasing protein degradation, which decreases tissue mass. However, the rate of protective autophagy declines with age. The inability to remove damaged structures results in the progressive accumulation of 'garbage', including abnormal intracellular proteins aggregates and undigested materials such as lipofuscin. Eventually, the progress of these changes results in enhanced oxidative stress, decreased ATP production, collapse of the cellular catabolic machinery, and cell death. By contrast, in load-induced heart failure, the extent of autophagic flux can rise to maladaptive levels. Excessive autophagy induction leads to autophagic cell death and loss of cardiomyocytes and may contribute to the worsening of heart failure. Accordingly, the development of therapies that up-regulate the repair qualities of the autophagic process and down-regulate the cell death aspects would be of great value in the treatment of heart failure.

Cardiac metabolism — A promising therapeutic target for heart failure

“…However, perhexiline has also been shown to inhibit the mammalian target of rapamycin complex 1 (mTORC1; Balgi, et al, 2009), an effect which is shared by amiodarone. The mTOR-signaling pathway relays signals of adequate energy supplies to inhibit cardiomyocyte autophagy, which is over-activated (due to AMPK activation, which inhibits mTOR; Matsui, et al, 2007) and maladaptive in the hypertrophic failing heart (De Meyer, et al, 2010). This ancillary property of perhexiline is likely to affect the careful balance of cardiac autophagy and therefore disease progression and prognosis in HF, however further investigation is needed to test this.…”

Emerging role of autophagy in kidney function, diseases and aging

“…The basal autophagy in the heart antagonizes ventricular hypertrophy by increasing protein degradation, which decreases the tissue mass. 265 The rate of protective autophagy in the heart declines with age, which is associated with an age-dependent decline in cardiac function. 265 Muscle weakness is also a harmful symptom in elderly individuals.…”

“…265 The rate of protective autophagy in the heart declines with age, which is associated with an age-dependent decline in cardiac function. 265 Muscle weakness is also a harmful symptom in elderly individuals. Mice lacking macroautophagy activity by deletion of the Atg7 gene in skeletal muscle show accumulation of abnormal mitochondria, which causes age-dependent muscle atrophy and a decrease in force.…”

Autophagy in Atherosclerosis

“…Preclinical studies have demonstrated that autophagy is associated with cancer, neurodegenerative disorders (eg, Alzheimer, Parkinson, and Huntington diseases), embryogenesis, aging, and immunity, and also with cardiovascular disease, including ischemia-reperfusion injury of the heart, cardiomyopathy, and atherosclerosis. [5][6][7][8][9] Despite tremendous recent advances in the field, the functional significance of autophagy in human disease remains incompletely understood and potentially involves both adaptive and maladaptive outcomes. Nonetheless, a growing body of evidence suggests that manipulation of the signaling pathways regulating autophagy provides novel therapeutic strategies in the prevention or treatment of human disease, as discussed for atherosclerosis in more detail below.…”