title: 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.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Lekli
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary.
authors.forename: David Donald
authors.initials: DD
authors.lastname: Haines
authors.affiliation: Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.|Hemostasis, Thrombosis and Vascular Biology Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Balla
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary.
authors.forename: Arpad
authors.initials: A
authors.lastname: Tosaki
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D001343:Autophagy / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics; D006801:Humans; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000503:physiopathology
chemical_list: D046988:Proteasome Endopeptidase Complex
keywords: autophagy; cardiovascular system; proteotoxic stress