Abstract 3614: Humanin Analog Improves Myocardial Survival and Cardiac Function via Activation of AMPK and Regulation of Apoptosis
Background: Humanin, an endogenous anti-apoptotic peptide, has been shown to protect against Alzheimer’s disease and various cellular insults. We evaluated the potential of a potent analog of humanin, HNG, to offer myocardial protection in an in vivo model of myocardial ischemia and reperfusion (MI-R).
Methods: Eight-week old male C57BL6/J mice were subjected to 45 min of left coronary artery occlusion followed by 24 hr reperfusion. HNG or vehicle was administered (intracardiac) at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hrs using Evans Blue dye and TTC. Cardiac function was evaluated at one week post ischemia using high-resolution 2-D echocardiography (Vevo 770). Molecular signaling pathways and apoptotic markers were assessed in the myocardium at various time points (0 –24 hrs) following reperfusion.
Results: HNG reduced infarct size relative to the area-at-risk in a dose dependent fashion, with a maximal (39%) reduction at a dose of 2 mg/kg (Fig 1a⇓). This dose was used in subsequent experiments. HNG therapy significantly improved ejection fraction (Fig 1b⇓), and decreased end systolic and diastolic volume, resulting in a significant improvement in cardiac function. In the HNG-treated animals, there was a significant increase in expression of pAMPK by 15 min (p<0.05) that persisted for 24 hrs. Furthermore, expressions of Bax, Bcl-2 and cleaved caspase-3 following MI-R were significantly attenuated by HNG.
Conclusion: HNG provides cardioprotection in a mouse model of MI-R through activation of AMPK and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.