Abstract P291: The Ubiquitin Ligase Siah2 in Cardiac Response to Ischemia

Abstract

Background: The E3 ubiquitin ligases SIah1 and 2 mediate a cellular response to hypoxia through its control of prolyl-hydroxylases and consequently HIF1α stability. Given the impact of hypoxia on heart function under stress, we have evaluated the effect of genetic deletion of Siah1 and 2 on cardiac function in response to myocardial infarction. Objective: To determine the physiological significance of the ubiquitin ligase Siah genes under in vivo ischemia condition. Materials and methods: To substantiate the role of Siah2 in ischemia-induced cell death, we tested difference in the response of myocardial tissue to ischemia using Siah1a +/− /Siah2 −/− mutant mice and their wildtype littermates. Analysis of heart tissue from Siah1a +/− /Siah2 −/− mice subjected to a model of 24 hours anterior descending coronary artery occlusion revealed their resistance to ischemic injury when compared with their littermates. Cardiac function, measured as EF %, was significantly less impaired in the mutant mice. Heart tissue obtained from Siah1a +/− /Siah2 −/− mice subjected to myocardial ischemia, exhibited a significantly lower degree of apoptosis (Tunel Staining), and myocardial infarct size (Evans blue, TTC). Conclusions: Collectively, these data establish that reduced expression of Siah1/2 exerts a cardioprotective function under ischemic conditions. The underlying molecular mechanisms linking cardioprotection to ischemic challenge will be discussed.