Although the prognosis of myocardial ischemia has been dramatically improved by the techniques of early reperfusion, the prevention of irreversible ischemic damage remains a critical aspect of the treatment. An appealing novel therapeutic avenue for the prevention of myocardial ischemia relates to the possibility of a pre- emptive conditioning of the heart, in which an activation of survival pathways could be achieved before potentially lethal ischemia occurs. Ischemic preconditioning represents the """"""""gold standard"""""""" method of cardioprotection in vivo but it remains difficult to use in the clinical setting. We propose that H11 kinase/Hsp22 (H11K) is both necessary and sufficient to reproduce the pattern of gene expression that characterizes the cardioprotection conferred by the """"""""delayed"""""""" or second window of ischemic preconditioning (SWOP). H11K is a chaperone expressed predominantly in the heart, the expression of which increases in various forms of ischemic heart disease, both in animal models and in patients. Increased expression of H11K in a cardiac- specific transgenic (TG) mouse to a level comparable to that found in models of heart disease is sufficient to provide protection against ischemia that is quantitatively similar to ischemic preconditioning. Based on the Preliminary Data, we have three goals. The first goal (Hypothesis 1: Molecular Mechanisms) is to better define the signaling pathway by which H11K promotes cardiac survival. We propose an original pathway in which the stimulation of the bone morphogenetic protein (BMP) receptor by H11K results in the activation of phosphatidylinositol-3 kinase (PI-3K) and the subsequent activation of the transcription factor NF-:B by Akt and the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). The second goal (Hypothesis 2: Physiological Relevance) is to rely on a knockout (KO) mouse model that we generated to prove that H11K is necessary for cardiac cell survival, and especially for the mechanisms of delayed preconditioning. The third goal (Hypothesis 3: Clinical Potential) is to determine whether short-term delivery of H11K in vivo is sufficient to promote cardiac cell survival in a context of lethal ischemia, which would lay the basis for validation of the concept of cardiac pre-emptive conditioning. We will combine an in vitro system (isolated cardiac myocytes and gene knockdown) with mouse models in vivo (TG and KO) and a pre-clinical model (gene delivery in the swine) to address these goals comprehensively.
PROJECT NARRATIVE Although the prognosis of myocardial ischemia has been dramatically improved by the techniques of early reperfusion, the prevention of irreversible ischemic damage remains a critical aspect of the treatment. An appealing novel therapeutic avenue for the prevention of myocardial ischemia relates to the possibility of a pre- emptive conditioning of the heart, in which an activation of survival pathways could be achieved in patients with ischemic heart disease who are at risk for a subsequent lethal ischemia. These patients would include those with unstable angina, or with severe and repetitive ischemic episodes, and patients scheduled for surgical revascularization. In these situations, the pre-emptive activation of survival signaling mechanisms would confer a prophylactic cardioprotection during the following ischemic stress.
