Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide.

Abstract

BACKGROUND:

Manifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the "no-reflow" phenomenon. Mitochondria-produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically.

METHODS AND RESULTS:

We investigated the cardioprotective effects of a mitochondria-targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (P=0.02) and in an ex vivo guinea pig model by 38% to 42% (P<0.05). In an in vivo rabbit model, the extent of coronary no-reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (P=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species-mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia-treated myocytes.

CONCLUSIONS:

Postischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria-targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels. (J Am Heart Assoc. 2012;1:e001644 doi: 10.1161/JAHA.112.001644.).

• Authors: Robert A Kloner, Sharon L Hale, Wangde Dai, Robert C Gorman, Takashi Shuto, Kevin J Koomalsingh, Joseph H Gorman 3rd, Ruben C Sloan, Chad R Frasier, Corinne A Watson, Phillip A Bostian, Alan P Kypson, David A Brown
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 1 Issue 3 Pg. e001644 (Jun 2012) ISSN: 2047-9980 [Electronic] England
• PMID: 23130143 (Publication Type: Journal Article)