Ischaemia and the myocyte cytoskeleton: review and speculation

Abstract

The cardiomyocyte cytoskeleton is composed of a highly organised complex array of specific proteins, arranged to transmit mechanical forces within the cell, to adjacent cells and the extracellular matrix, as well as to maintain internal organisation of cellular organelles. Although most of the published reports on cytoskeletal proteins refer to non-myocyte and smooth muscle cells, there seem significant homologies with cardiac structures. The specific interactions of some proteins in certain cytoskeletal structures are established and may be analogous to interactions in cardiac myocytes, but the roles of many proteins are uncertain, and the list of proteins that compose the cytoskeleton is likely to be incomplete. Some proteins may serve a dual role, contributing to signal transduction as well as to organisation and mechanical stability of the cell. Phosphorylation of cytoskeletal proteins, and elaborate cellular systems to control protein phosphorylation levels, suggest phosphorylation as a potential mechanism of controlling cytoskeletal assembly and remodelling. Disturbances of the cytoskeleton during ischaemia may produce alterations in cell structural integrity that could account for cell injury and death. Although mechanisms both of cytoskeletal assembly in normal cells and of cytoskeletal injury in ischaemic cells are currently poorly understood, research into the interactions of cytoskeletal proteins during ischaemia includes new approaches that may increase our understanding of the pathophysiology of the cardiac myocyte.

Protein phosphatase inhibitors and heat preconditioning prevent Hsp27 dephosphorylation, F‐actin disruption and deterioration of morphology in ATP‐depleted endothelial cells

“…A severe fall of cellular ATP is one of the most detrimental consequences of ischemia or anoxia that deranges the cytoskeleton and its interactions with the plasma membrane, thus dramatically affecting cell morphology and viability (see for review [1,2]). Organization of microfilaments and their contacts with the plasma membrane are mainly regulated by protein kinases and protein phosphatases (PP) via phosphorylation/dephosphorylation of actin-associated and regulatory proteins [1,3].…”

“…Organization of microfilaments and their contacts with the plasma membrane are mainly regulated by protein kinases and protein phosphatases (PP) via phosphorylation/dephosphorylation of actin-associated and regulatory proteins [1,3]. Depletion of ATP in cells during ischemia or anoxia may shift the balance between phosphorylation and *Corresponding author.…”

“…Indeed, anoxia in rabbit proximal renal tubules completely suppressed protein phosphorylation, whereas protein dephosphorylation was unchanged or enhanced [4]. Such abnormal prevalence of protein dephosphorylation over phos-.phorylation was suggested as a probable cause of the cytoskeletal collapse under ischemia or anoxia [1,[4][5][6]. In support of this suggestion, dephosphorylation of two actin-regulating proteins, ezrin in anoxic rabbit proximal renal tubules [5] and the 27-kDa heat shock protein (Hsp27) in ATP-depleted human endothelial cells (EC) [6], was shown to occur and, in both cases, this was accompanied by disorganization of microfilaments.…”

Stressful preconditioning and HSP70 overexpression attenuate proteotoxicity of cellular ATP depletion

“…chaperone; protein aggregation; metabolic stress; ischemic tolerance AT THE CELLULAR LEVEL, failing energy metabolism and ATP depletion are the earliest cell-damaging factors of ischemic insults. In vivo, severe depletion of ATP is a proteotoxic stress that leads to dysfunction, destabilization, and aggregation of many cellular proteins, including enzymes, ion pumps, and constituents of cytoskeletal and contractile structures (1,9,17,27). Sustained lack of ATP is obviously lethal for the cell.…”

Impact of Ischemia on Cellular Metabolism

“…Destruction of the internal architecture worsens I/R injuries and leads to apoptosis. [53], [56], [57] During ischemia, all elements of the cytoskeleton are affected, but with different kinetics. [54], [55] Moreover, the accumulation of osmotically active particles, including lactate, sodium, inorganic phosphate and creatine, induces cellular oedema.…”