Preconditioning in the absence or presence of sustained ischemia modulates myocardial Cx43 protein levels and gap junction distribution

Abstract

In the heart, brief repeated episodes of ischemia prior to a sustained occlusion (ischemic preconditioning; PC) significantly delay the onset of necrosis and arrhythmogenesis. Ischemia has been reported to influence gap junction organization and connexin43 (Cx43) content, but whether PC affects these structures is not known. We investigated the effect of PC (2 cycles of 5-min ischemia plus 10-min reperfusion) followed by prolonged reperfusion without concomitant regional coronary occlusion on the myocardial Cx43 content and its spatial distribution in rabbit hearts. We also compared the effect of sustained ischemia with or without PC on Cx43 spatial distribution. In experiments with PC only, there was an initial decrease in Cx43 levels within the ischemic zone followed by a progressive increase after 48 h reperfusion. End-to-end immunolabeling of Cx43 was augmented in the ischemic region between 24 and 48 h reperfusion; labeling was not uniquely confined to myocyte abutments, but was also dispersed along the sarcolemma. Cx43 immunolabelling was more intense and diffuse in hearts subjected to PC before sustained coronary occlusion (compared to non-PC). These data indicate that gap junctions are significantly altered during brief episodes of ischemia. Reorganization of the gap junction complex could contribute to PC-mediated reductions in cardiac arrhythmias.

Coronary vasoregulation in health and disease

“…Changes in the organization of cytoskeletal proteins are reported to be involved in gap junction assembly and migration (60). In studies by Daleau et al (61), a spatial reorganization of the gap junction complex was documented that may contribute to IPC-mediated limitations in cardiac arrhythmias. Kingma (58) reported the rapid induction of cytoprotective genes that are part of the stress protein family and nuclear proto-oncogenes following IPC in rabbit hearts.…”

A Central Role of Connexin 43 in Hypoxic Preconditioning

“…Previous work has documented that cellular injury is linked to an upregulation of Cx43 expression in a variety of cells and tissues (Daleau et al, 2001;VanSlyke and Musil, 2005). For example, alveolar epithelial cells increased Cx43 expression after radiation (Kasper et al, 1996), smooth muscle cells exhibited increased Cx43 levels after balloon catheter injury of rat carotid artery (Yeh et al, 1997), multiple Cxs were upregulated after peripheral nerve injury (Chandross, 1998;Chang et al, 2000;Lin et al, 2002), and one of the earliest responses to kidney damage is an increase of Cx43 expression (Yaoita et al, 2002).…”

Dysregulation of Cell Adhesion Proteins and Cardiac Arrhythmogenesis

“…[18][19][20] Disturbances in the distribution of gap junctions and reduced levels of Cx43 occur not only in association with established infarct scar tissue in the human heart, but have been shown in experimental animals to be initiated rapidly after ventricular ischemia and infarction. 4,21,22 Alterations in connexin expression and spatial remodeling of gap junctions in regions bordering healing infarcts have been implicated in the development of slow, heterogeneous conduction and conduction block critical in reentrant arrhythmogenesis. 22 More widespread spectacular disordered arrangements of ventricular Cx43 gap junctions are an inevitable consequence of the haphazard myocyte organization characteristic of human hypertrophic cardiomyopathy, the most common cause of SCD due to arrhythmia.…”