Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice.

Abstract

OBJECTIVE:

Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion.

METHODS AND RESULTS:

Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro.

CONCLUSIONS:

These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

• Authors: Radhika H Muzumdar, Derek M Huffman, John W Calvert, Saurabh Jha, Yoni Weinberg, Lingguang Cui, Anjana Nemkal, Gil Atzmon, Laura Klein, Susheel Gundewar, Sang Yong Ji, Madhav Lavu, Benjamin L Predmore, David J Lefer
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 10 Pg. 1940-8 (Oct 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20651283 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bax protein, mouse
• Gly(14)-Humanin
• Intracellular Signaling Peptides and Proteins
• Peptides
• bcl-2-Associated X Protein
• humanin
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Ischemia (drug therapy, pathology, physiopathology)
• Myocardial Reperfusion Injury (drug therapy, pathology, physiopathology)
• Myocytes, Cardiac (drug effects, pathology)
• Nitric Oxide Synthase Type III (metabolism)
• Peptides (therapeutic use)
• Signal Transduction (drug effects)
• bcl-2-Associated X Protein (metabolism)