COMP-Ang-1 treatment significantly improved cardiac function after myocardial ischemia/reperfusion injury, resulting in a higher ejection fraction of 48.05% compared to 31.4% in the control group.
Does angiopoietin-1 improve cardiac function and reduce vascular leakage and cardiomyocyte death in ischemia/reperfusion injury models?
Angiopoietin-1 protects against myocardial ischemia/reperfusion injury by reducing vascular leakage via VE-cadherin dephosphorylation and preventing cardiomyocyte apoptosis via the integrin-β1/ERK/caspase-9 pathway.
Absolute Event Rate: 48.05% vs 31.4%
p-value: p=<0.05
Early reperfusion after myocardial ischemia that is essential for tissue salvage also causes myocardial and vascular injury. Cardioprotection during reperfusion therapy is an essential aspect of treating myocardial infarction. Angiopoietin-1 is an endothelial-specific angiogenic factor. The potential effects of angiopoietin-1 on cardiomyocytes and vascular cells undergoing reperfusion have not been investigated. We propose a protective mechanism whereby angiopoietin-1 increases the integrity of the endothelial lining and exerts a direct survival effect on cardiomyocytes under myocardial ischemia followed by reperfusion. First, we found that angiopoietin-1 prevents vascular leakage through regulating vascular endothelial (VE)-cadherin phosphorylation. The membrane expression of VE-cadherin was markedly decreased on hypoxia/reoxygenation but was restored by angiopoietin-1 treatment. Interestingly, these effects were mediated by the facilitated binding between SH2 domain-containing tyrosine phosphatase (SHP2) or receptor protein tyrosine phosphatase μ (PTPμ) and VE-cadherin, leading to dephosphorylation of VE-cadherin. siRNA against SHP2 or PTPμ abolished the effect of angiopoietin-1 on VE-cadherin dephosphorylation and thereby decreased levels of membrane-localized VE-cadherin. Second, we found that angiopoietin-1 prevented cardiomyocyte death, although cardiomyocytes lack the angiopoietin-1 receptor Tie2. Angiopoietin-1 increased cardiomyocyte survival through integrin-β1-mediated extracellular signal-regulated kinase (ERK) phosphorylation, which inhibited caspase-9 through phosphorylation at Thr¹²⁵ and subsequently reduced active caspase-3. Neutralizing antibody against integrin-β1 blocked these protective effects. In a mouse myocardial ischemia/reperfusion model, angiopoietin-1 enhanced cardiac function and reduction in left ventricular-end systolic dimension (LV-ESD) and left ventricular-end diastolic dimension (LV-EDD) with an increase in ejection fraction (EF) and fractional shortening (FS). Our findings suggest the novel cardioprotective mechanisms of angiopoietin-1 that are achieved by reducing both vascular leakage and cardiomyocyte death after ischemia/reperfusion injury.
Lee et al. (Tue,) conducted a other in Myocardial ischemia/reperfusion injury. COMP-Ang-1 (cAng-1) vs. Ad-β-gal was evaluated on Ejection fraction at 4 weeks (p=<0.05). COMP-Ang-1 treatment significantly improved cardiac function after myocardial ischemia/reperfusion injury, resulting in a higher ejection fraction of 48.05% compared to 31.4% in the control group.