The role of autophagy in cardiac damage

Abstract

Autophagy is one of the mechanisms ensuring cell homeostasis on the one hand, and on the other hand, it is a way of utilizing damaged cell structures through their autolysis in the autophagosome for reuse in cell metabolism. Autophagy is usually considered as an adaptive process allowing cells to survive under conditions of stress, nutrient deficiency and hypoxia. However, under certain circumstances autophagy can be the cause of cell death. Cell death accompanied by autophagy activation and autophagosome accumulation has been classified as programmed cell death type II. However, compared to detailed information on the adaptive role of autophagy, its involvement in cell death has been poorly understood. Autophagic cell death can be divided into two groups, namely: (1) autophagic cell death with increased autophagy activity; (2) autophagic cell death with decreased autophagy processes. In the first scenario, autophagy is excessively activated, causing uncontrolled autolysis of cellular structures and cell death. A similar scenario is observed in cell death caused by excessive degradation of damaged organelles in lysosomes. Of particular interest is a specific form of autophagy in which damaged mitochondria are excessively eliminated from the cell - mitophagy. Autophagic cell death is characteristic of diabetic cardiomyopathy. The second variant, characterized by reduced autophagy processes, is observed in doxorubicin-induced cardiomyopathy, autophagy during ischemia/reperfusion and autophagic cell death in lysosomal accumulation diseases. In this scenario, the final step of autophagy is usually disrupted, and an imbalance between autophagosome formation and lysosomal activity leads to massive autophagosome accumulation, which subsequently causes cellular dysfunction and death. Dysregulation of autophagy causes a unique form of cell death, called autosis, with certain morphological and biochemical features that differ from other forms of cell death, such as apoptosis and necrosis. In autosis, Na+/K+ ATPase plays a special role, which by physically interacting with Beclin 1 can promote autophagic cell death. The principles of therapeutic intervention aimed at preventing autophagic death of cardiomyocytes depend on the specific mechanisms of autophagy. For example, the use of Na+/K+-ATPase inhibitors, such as cardiac glycosides, provides a cardioprotective effect by inhibiting autophagy, while the use of trehalose and 3,4-dimethoxychalcon, can optimize autophagy processes and reduce the intensity of excessive autophagosome accumulation. Thus, the study of mechanisms of autophagy and search for new approaches in pharmacocorrection and pharmacoprophylaxis of autophagic cell death are actual directions of modern scientific research. The aim of the review is to present the concept of autophagic cell death in some heart diseases.