Cytoskeletal Proteins

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp arcolemmal rupture, a hallmark of cardiomyocyte necrosis after ischemia -reperfusion, is induced by an increase in sarcolemmal fragility during ischemia, as well as by mechanical stress on the sarcolemma imposed by cell edema and the restoration of contraction upon reperfusion. 1 How ischemia induces fragility of the sarcolemma remains unclear, but a putative mechanisms is loss of cytoskeletal proteins. Long-sustained ischemia reduces sarcolemmal levels of dytrophin, β-dytroglycan, γ-sarcoglycan, vinculin, spectrin and vinculin, and dystrophin is the most sensitive of these structural proteins to ischemia. 2-4 Dystrophin connects F-actin in the subsarcolemmal cytoskeleton or the sarcomeres to δ-dystroglycan spanning the cell membrane, and is a member of the dystrophin glycoprotein complex (DGC). 5 Ischemia induces translocation of dystrophin from the sarcolemma to the intracellular pools, and this ischemiainduced loss of dystrophin in the sarcolemma has been shown to correlate with formation of sarcolemmal blebs. 2 On the other hand, in isolated cardiomyocytes the loss of spectrin from the sarcolemma has correlated with fragility of the cell to hypo-osmotic stress. 2 However, these findings do not necessarily indicate that loss of dystrophin and/or spectrin is sufficient for priming cardiomyocytes for sarcolemmal rupture upon reperfusion. Article p 2393Dystrophin and other members of the DGC are crucial for physiological regulation of membrane permeability. In myocardium in which dystrophin or sarcoglycans is genetically deleted, permeability of the sarcolemma assessed by influx of cell-impermeable tracers (eg, Evans Blue [EB] and albumin) is significantly increased. 5,6 Intracellular Ca 2+ levels are elevated in these cardiomyocytes possibly by upregulation of the Ca 2+ -permeable, growth-factor-regulated channel (TRPV2). 7 Ca 2+ influx via this channel potentially aggravates cell injury by activation of a Ca 2+ -activated protease, calpain, leading to a vicious cycle of loss of structural membrane protein, increased sarcolemmal instability and Ca 2+ overload. This vicious cycle has been proposed as a mechanism of progressive cell loss and heart failure in animals and patients with mutations in the DGC. 5, 6 Otani et al have conducted a series of studies to address the causative relationship between dystrophin loss from the sarcolemma during ischemia and reperfusion-induced cardiomyocyte necrosis. 4,8-10 They first showed in the rat myocardium that approximately 60% of membrane dystrophin was lost after 30 min of ischemia and that further loss of dystrophin occurred after reperfusion. 4 Inhibition of ventricular contraction by 2,3-butanedione monoxime (BDM) during reperfusion did not affect the loss of sarcolemmal dystrophin, but did inhibit the increase in sarcolemmal permeability to EB after reperfusion, indicating that mechanical stress is crucial for the pathological increase in sarcolemmal permeability upon re...