Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts

Abstract

Although the phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway is essential for conferring cardioprotection in response to ischemic preconditioning (IP), the role of PI3K/Akt signaling in the infarcted heart for mediating the anti-arrhythmic effects in response to IP remains unclear. We explored the involvement of PI3K/Akt in the IP-like effect of connexin 43 and proangiogenic factors with particular regard to its role in protecting against ischemia-induced arrhythmia, heart failure, and myocardial remodeling. Groups of pigs were administered phosphate-buffered saline (PBS) or LY294002 solution. Before induction of myocardial infarction (MI), pigs were grouped according to whether or not they underwent IP. Next, all animals underwent MI induction by ligation of the left anterior descending (LAD) coronary artery. Myocardial tissues from the pig hearts at 7 days after MI were used to assess myocardium myeloperoxidase and reaction oxygen species, infarct size, collagen content, blood vascular density, expression of Akt, connexin 43, and proangiogenic growth factors, using spectrophotometer, histology, immunohistochemistry, real-time RT-PCR, and western blot. At 7 days after MI, IP significantly reduced animal mortality and malignant ventricular arrhythmia, myocardial inflammation, infarct size, and collagen content, and improved cardiac function and remodeling; use of the PI3K inhibitor LY294002 diminished these effects. In parallel with a decline in Akt expression and phosphorylation by MI, LY294002 injection resulted in significant suppression of connexin 43 and proangiogenic factor expression, and a reduction of angiogenesis and collateral circulation. These findings demonstrate that the cardioprotective effects of IP on antiventricular arrhythmia and myocardial repair occur through upregulation of PI3K/Akt-mediated connexin 43 and growth factor signaling. Sudden cardiac death comprises over 10% of all deaths from natural causes and constitutes a major health-related problem worldwide. In ∼ 80% of cases, sudden cardiac death is caused by sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) secondary to acute myocardial infarction (AMI). 1 Reducing malignant ventricular arrhythmia in infarcted hearts may be a key factor for improving prognosis of patients with MI. The strategy of myocardial repair using ischemic preconditioning (IP) provides an enticing option to reduce the severity of arrhythmias associated with AMI. Since its first description, myocardial IP has been found to enhance cardiac electrical stability in both animals and humans. However, the precise antiarrhythmic mechanisms underlying this adaptive process during ischemia are not well understood. It is generally thought that IP is able to limit the mass of myocardium at risk that ultimately becomes infarcted and results in reducing lethal arrhythmia. 2,3 However, lack of IP enhanced inflammatory response, and subsequent left ventricle (LV) dysfunction, are related to VT/VF development after AMI. 4 It has also been reported that c...

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