Vascular protection by HGF/IgG protein complexes that activate RYK

University Of Vermont & St Agric College, Burlington VT

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Abstract

? DESCRIPTION: The Central Hypothesis is treatment regimes that protect vascular integrity early after reperfusion will reduce infarct expansion, final infarct size, and adverse cardiac remodeling in hearts with myocardial infarction. A no re-flow phenomenon is commonly observed in experimental animals with myocardium subjected to ischemia followed by reperfusion and in patients with acute myocardial infarction (MI). No re-flow refers to compromised distal myocardial perfusion despite restoration of patency in proximal macroscopic vessels. The extent of no re-flow is a determinant of infarct expansion. No re-flow may result from destruction of microscopic vessels, which we have termed vascular rhexis, or from other factors such as microemboli, inflammation, release of toxic cellular metabolites, and oxidative stress that cause endothelial cell dysfunction and induce microvascular leaks. This proposal is based on the concept that treatments designed to improve blood supply by preventing vascular rhexis associated with ischemia and reperfusion will reduce no re-flow and diminish infarct size, adverse ventricular remodeling and dysfunction after MI. SPECIFIC AIMS: 1. Determine whether treatment with HGF/IgG complexes at the time of reperfusion can promote vascular integrity and reduce infarct expansion in a large animal model of MI. 2. Identify signaling pathway(s) activated by HGF/IgG complexes that confer enhanced vaso- protection after MI. 3. Determine whether sustained treatment with HGF/IgG complexes after MI provides long- term improvement in cardiac function by increasing cardiac perfusion and reducing infarct expansion, final infarct size, and/or adverse ventricular remodeling.