A1-ADRENERGIC RECEPTORS PREVENT PATHOLOGIC VENTRICULAR REMODELING FOLLOWING MI

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to define a protective role of the a1A-adrenergic receptor (a1A-AR) in ventricular remodeling following myocardial infarction. The neurohormonal hypothesis suggests that pathologic ventricular remodeling in heart failure is due to increased sympathetic activity and catecholamine release. Moreover, increased norepinephrine levels correlate with heart failure, predicting disease severity and mortality, thereby providing the foundation for the successful use of a-AR antagonists, or a-blockers, to treat heart failure. However, catecholamines also activate a1-ARs, and in two clinical trials, V-HeFT and ALLHAT, a1-blockers increased mortality and heart failure. Although the cardiac myocytes expresses both the a1A- and a1B-subtypes, work from our lab and others suggest that only the a1A-subtype is protective. However, it is unknown whether activation of the a1A-subtype in a pathological setting will prevent heart failure and improve survival. This project will test the hypothesis that the a1A-subtype protects the heart from pathologic ventricular remodeling following myocardial infarction by preventing myocyte death and inducing positive inotropic responses. To test this hypothesis Aim 1 will examine ventricular remodeling following coronary artery occlusion in cardiac-specific a1A-transgenic mice. Aim 2 will examine a1A-subtype mediated survival signaling in response to hypoxia in cultured myocytes, as well as the role of ERK in a1-survival signaling in response to hypoxia, both in cultured myocytes and in vivo. Aim 3 will examine contractile function in myocytes isolated from a1A-transgenic mice following coronary artery occlusion and if the a1A-subtype prevents contractile dysfunction in response to hypoxia in cultured myocytes.