Abstract
Ischemia reperfusion (I/R)-induced arrhythmia is a serious complication in patients with cardiac infarction. Remodeling of connexin (Cx) 43, manifested as phosphorylation, contributes significantly to arrhythmogenesis. Integrin-linked kinase (ILK) attenuated ventricular remodeling and improved cardiac function in rats after myocardial infarction. We hypothesized that ILK, through Cx43 phosphorylation, would be protective against I/R-induced ventricular arrhythmias. Our study showed that I/R-induced ventricular arrhythmias were attenuated by an ILK agonist LPTP and worsened by the ILK inhibitor Cpd22. I/R disrupted Cx43 distribution, but it was partially normalized in the presence of LPTP. Compared with I/R, the phosphorylation of Akt was increased significantly after pretreatment with LPTP. The increase in phosphorylated Akt was physiologically significant because, in the presence of the Akt inhibitor MK2206, the protective effects of LPTP were blocked. This indicated that ILK activation prevented I/R-induced-ventricular arrhythmia, an effect potentially related to inhibition of Cx43 remodeling via Akt activation.
Highlights
Ischemic heart disease is among the most prevalent worldwide health problems [1]
Integrin-linked kinase (ILK) inhibitor Cpd22 could increase the arrhythmia score after reperfusion (5.0 ± 1.2 vs 3.5 ± 1.5, P < 0.05); Cpd22 could abolish the effect of LPDT on arrhythmia score (3.6 ± 1.7 vs 1.7 ± 1.3, P < 0.05) (Fig. 1a)
Cpd22 extended the duration of ventricular tachycardia (VT) + ventricular fibrillation (VF) compared with the I/R group (P < 0.05)
Summary
Ischemic heart disease is among the most prevalent worldwide health problems [1]. It is caused primarily by coronary occlusion, which leads to tissue hypoxia, cellular necrosis, and apoptosis. Reperfusion after coronary occlusion is proven as the most efficient way to improve cardiac function and decrease infarct size. Reperfusion arrhythmia is an important marker of successful reperfusion of an occluded coronary artery, it is a major clinical manifestation leading to cardiac death. To overcome the effects of severe ventricular arrhythmias in ischemia-reperfusion (I/R) injured hearts is a major challenge. It is important to clarify the underlying mechanism(s) of I/R-induced cardiac arrhythmia
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