Redistribution of connexin43 in regional acute ischemic myocardium: influence of ischemic preconditioning

Abstract

Connexins are known to play an essential role in the ischemic preconditioning (IP) of the heart; their functional role in this process, however, has not been clearly defined. For this reason, anesthetized rats were subjected to regional myocardial ischemia, with or without IP or reperfusion. In frozen sections of hearts, fluorescence immunohistochemical staining for connexin43 (Cx43) was performed. In contrast to undisturbed zones, tissue that had been subjected to ischemia revealed Cx43 immunostaining not only in the gap junctions but also in a conspicuous pattern in the free cellular membranes of the myocytes. In myocardium that was exposed to IP only, the ratio of immunofluorescence intensity in the free cellular membrane to that in the interior of the cell was 1.22 +/- 0.04 (ratio in non-ischemia-exposed area = 1.04 +/- 0.01). When 15 or 45 min of permanent ischemia followed IP, the effect became more evident (ratio = 1.31 +/- 0.03 and 1.46 +/- 0.03, respectively) and proved to be significantly greater than in the corresponding non-IP groups (ratio = 1.16 +/- 0.03 and 1.30 +/- 0.03, respectively, P< 0.01). Reperfusion led to an overall weakening of fluorescence intensities and a disappearance of the observed IP-specific differences. We conclude that IP initiates a redistribution of Cx43 from its natural position in the gap junctions toward the free plasma membrane, thereby improving the cell's chance of survival during the subsequent phase of prolonged ischemia by an unknown, supposedly gap junction-independent, mechanism.

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

“…Inhibition of gap junctions during ischemia or reperfusion reduced infarct size (30,31), suggesting a possible protective effect by impeding spread of damaging metabolites via cell-cell contacts, which, however, remains controversial, given that ischemia, per se, initiates closure of gap junctions (32). Ischemia induces redistribution of Cx43 to the lateral wall of cardiomyocytes and may open these Cx43 hemichannels, which has been proposed to contribute to reperfusion injury (33)(34)(35). Notably, IP also suppresses gap junction permeability and induces Cx43 lateralization (31,33).…”

“…Ischemia induces redistribution of Cx43 to the lateral wall of cardiomyocytes and may open these Cx43 hemichannels, which has been proposed to contribute to reperfusion injury (33)(34)(35). Notably, IP also suppresses gap junction permeability and induces Cx43 lateralization (31,33). However, in this setting, the addition of gap junction inhibitors is deleterious (i.e., abolishes protection afforded by IP) (31).…”

A Central Role of Connexin 43 in Hypoxic Preconditioning

“…The preconditioned heart exhibited a higher level of Cx43 and redistribution of Cx43-immunoreactive plaques (Daleau et al, 2001;Vetterlein et al, 2006). Cx43 was not confined to myocyte abutments, as in normal heart, but was dispersed diffusely along the sarcolemma after preconditioning (Daleau et al, 2001;Vetterlein et al, 2006).…”

“…However, the impact of Cx expression extends beyond bystander death, because expression of Cx43, Cx36, Cx32, or Cx26 increased cellular injury resistance in a gap junction-independent pathway (Oguro et al, 2001;Lin et al, 2003;Striedinger et al, 2005). The phenotypic transformation that increases the injury threshold of Cx-expressing cells has not been established (Lin et al, 2003;Vetterlein et al, 2006) but may be similar to preconditioning involving efflux of neuroprotective agents through open hemichannels. Depending on the severity of injury, physiological parameters of the animal, or the experimental design, bystander death may outstrip adenosine-mediated neuroprotection or vice versa.…”

Loss of Anti-Arrhythmic Effect of Vagal Nerve Stimulation on Ischemia-Induced Ventricular Tachyarrhythmia in Aged Rats

“…Previous studies have shown that intercellular electrical uncoupling plays an important role in arrhythmogenesis during acute myocardial ischemia (MI) (Smith et al 1995;Saffitz et al 1999;Beardslee et al 2000). The amount and distribution of Cx43 in the ventricles are significantly altered during ischemia Gutstein et al 2001;Vetterlein et al 2006). Previous studies have shown that Cx43 undergoes prominent dephosphorylation in ischemia-induced electrical uncoupling (Papp et al 2007;Jiang et al 2008), suggesting that the changes of Cx43 may contribute to the pathogenesis of ventricular arrhythmias during acute MI.…”