Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion‐associated cardiac arrhythmias

Abstract

Oxidative stress placed on tissues that involved in pathogenesis of a disease activates compensatory metabolic changes, such as DNA damage repair that in turn causes intracellular accumulation of detritus and ‘proteotoxic stress’, leading to emergence of ‘senescent’ cellular phenotypes, which express high levels of inflammatory mediators, resulting in degradation of tissue function. Proteotoxic stress resulting from hyperactive inflammation following reperfusion of ischaemic tissue causes accumulation of proteinaceous debris in cells of the heart in ways that cause potentially fatal arrhythmias, in particular ventricular fibrillation (VF). An adaptive response to VF is occurrence of autophagy, an intracellular bulk degradation of damaged macromolecules and organelles that may restore cellular and tissue homoeostasis, improving chances for recovery. Nevertheless, depending on the type and intensity of stressors and inflammatory responses, autophagy may become pathological, resulting in excessive cell death. The present review examines the multilayered defences that cells have evolved to reduce proteotoxic stress by degradation of potentially toxic material beginning with endoplasmic reticulum‐associated degradation, and the unfolded protein response, which are mechanisms for removal from the endoplasmic reticulum of misfolded proteins, and then progressing through the stages of autophagy, including descriptions of autophagosomes and related vesicular structures which process material for degradation and autophagy‐associated proteins including Beclin‐1 and regulatory complexes. The physiological roles of each mode of proteotoxic defence will be examined along with consideration of how emerging understanding of autophagy, along with a newly discovered regulatory cell type called telocytes, may be used to augment existing strategies for the prevention and management of cardiovascular disease.

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

“…Autophagy is an evolutionarily conserved pathway that targets cytoplasmic contents (eg, organelles or protein aggregates) to the lysosome for degradation . Although some controversies exist, most reports in the literature show insufficient autophagy during DCM .…”

“…Autophagy is an evolutionarily conserved pathway that targets cytoplasmic contents (eg, organelles or protein aggregates) to the lysosome for degradation. 4,5,36 Although some controversies exist, most reports in the literature show insufficient autophagy during DCM. [37][38][39][40] Our previous study also indicated that cardiomyocyte autophagy was downregulated as evidenced by decreased LC3-II expression and increased p62/aggresome accumulation in the diabetic heart.…”

“…3 Autophagy is a self-degradative and recycling process which primarily targets long-lived cytoplasmic proteins. 4 The physiological protein degradation through autophagy maintains the intracellular environment. 5,6 Functional disorders of autophagy participate in many cardiometabolic disorders.…”

The role of mitochondria in the myocardium of senescent Meriones unguiculates

“…Згідно з вільнорадикальною теорією, у процесі старіння відбувається наростання молекулярних пошкоджень мембран і генетичного апарату клітини, послаблення активності захисних механізмів (Josq Maryn-Garcya, 2005;Hayat, 2014;Lekli et al, 2017). Одна з основних причин такого явищаінтенсивна генерація активних форм оксигену.…”

“…Надлишкове утворення перекисних продуктів викликає накопичення дисфункціональних і аномальних мітохондрій, що визначається важливою патофізіологічною особливістю старіння серця (Ikeda et al, 2014;Zhao et al, 2014). У похилому віці знижується ефективність репараційних процесів, а саме аутофагія / мітофагія, тобто видалення пошкоджених, не функціональних мітохондрій (Hayat, 2014;Lekli et al, 2017).…”