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.
Highlights
Ia - Inflammatory tissue damage, disease and trauma
The major symptoms of cardiovascular disease, including ventricular fibrillation (VF), which are often initiated by IRassociated oxidative damage, may be exacerbated by hypertrophic cell growth resulting from greatly elevated activation of a serine/threonine kinase responsible for synthesis of cell components called mammalian target of rapamycin [19]
As described in the foregoing sections, autophagy is a potent adaptive mechanism for maintaining healthy cellular homeostasis by clearing toxic cellular debris and allowing cells that might otherwise die to survive in functional forms that do not pose a hazard to surrounding tissue
Summary
Larger categories of detritus are subject to degradation and recycling via macroautophagy, in which damaged or unusable proteins and cellular organelles become enclosed by double-walled membrane vesicles called autophagosomes, and fused with lysosomes for degradation and recycling [30] This process, mediated mainly by ubiquitin and enzyme-containing complexes called ULK and Beclin1–PI3KC3, is the form of autophagy most frequently utilized by cells for clearance of detritus in a size range capable of severely disrupting cellular homeostasis [31,32,33] – and constitutes the form of autophagy most frequently described as a major cellular countermeasure to accumulation of toxic protein aggregates [34,35]. Autophagic activity resulting in cell survival appears to be a significant factor in the amount of tissue that may survive for prolonged periods in chronically ischemic myocardium [39,40] This protective effect may be abolished with autophagy-inhibiting drugs such as wortmannin [41,42,43]. Under conditions of extreme tissue stress, high levels of autophagy may initiate cascades of pathological reactions in myocardial cells and, deterioration of myocardial function [44]
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