ucf-101 and Ventricular-Dysfunction--Left

High temperature requirement A2 (HtrA2)/Omi is a mitochondrial serine protease that is released into the cytosol from mitochondria and in turn promotes caspase activation by proteolyzing inhibitor of apoptosis proteins. Here we asked whether treatment with an HtrA2/Omi inhibitor, 5-[5-(2-nitrophenyl)furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101), restores heart dysfunction following ischemia/reperfusion injury in vivo. Rats underwent a 30-min ischemia by occluding the left anterior descending artery, followed by 24 h reperfusion. UCF-101 (0.75 or 1.5 micromol/kg, i.p.) was administered 10 min before reperfusion. UCF-101 treatment significantly recovered the mean arterial blood pressure and ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion with concomitant reduction of infarct size. Cardio-protection mediated by UCF-101 was correlated with reduced X-linked inhibitor of apoptosis protein (XIAP) degradation and inhibition of Caspase-9, Caspase-3, and Caspase-7 processing. Furthermore, UCF-101 prevented loss of membrane integrity by inhibiting fodrin breakdown in cardiomyocytes. UCF-101-induced cytoprotection was also correlated with reduced Fas ligand expression and inhibition of FLIP degradation following ischemia/reperfusion. These results suggest that UCF-101 rescues cardiomyocytes from ischemia/reperfusion injury by inhibiting XIAP degradation and Fas/Fas-ligand-induced apoptosis, thereby ameliorating ischemia/reperfusion-induced myocardial dysfunction.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase Inhibitors; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Fas Ligand Protein; Heart; High-Temperature Requirement A Serine Peptidase 2; Kinetics; Male; Microfilament Proteins; Mitochondrial Proteins; Models, Cardiovascular; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Nerve Tissue Proteins; Pyrimidinones; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; Serine Endopeptidases; Serine-Arginine Splicing Factors; Thiones; Ventricular Dysfunction, Left; X-Linked Inhibitor of Apoptosis Protein