Electrical Remodeling and Cardiac Hypertrophy and Signaling

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DESCRIPTION (provided by applicant): Heart failure is a major cause of morbidity and mortality in the United States. The purpose of this Mentored Minority Faculty Development Award (K01) is to prepare the applicant for a career as an independent investigator in the area of cardiac hypertrophy and heart failure. The applicant has developed a great interest in the disorders of cardiac excitability and cellular dysfunction observed in heart failure. The applicant proposes to acquire additional skills in somatic gene transfer, electrophysiology and in vivo cardio-physiology in the context of a project that will promote the development of the intellectual skills necessary for success as an independent investigator. Heart failure is a highly lethal syndrome worldwide with as many as 50% of affected patients dying suddenly. At the cellular level, reduction of the calcium-independent transient outward current (Ito0 and prolongation of the action potential duration (APD) is consistently observed in experimental animal models of cardiac hypertrophy and failure and human heart failure. In hypertrophied myocytes Itol is decreased secondary to reductions in the expression of Kv4.2 and Kv4.3 potassium channel genes and more recently to the K channel interacting protein (KChlP2). The proposed project is intended to decipher the role of calcium entry via L-type calcium channels secondary to manipulation of the potassium channel genes encoding for Ito_ and the potassium channel interacting protein. We hypothesize that: 1) APD prolongation plays an important role in the progression of hypertrophy and failure once cardiac hypertrophy is initiated, 2) that elevations in systolic [Ca 2+] can activate the "stress signaling pathways" such as calcineurin and MAPKinase pathways leading to alterations in gene expression and hypertrophy, and 3) that the potassium channel interacting protein plays a an important modulatory role in the hypertrophic process. We will use adenoviral gene transfer to introduce Kv4.2, Kv4.3, and KChIP2 into aortic-banded rat hearts. We will measure electrophysiologic and Ca 2+ and hemodynamics parameters and use an animal model of pressure overload to determine the effects of 1) Kv channel and KChIP manipulation on Itol and APD in vitro and in vivo and 2) the signaling pathways on the response to hypertrophy and failure. Understanding the role of K+ channels in signal transduction will lead to the design of specific drugs to target these channels and block the development of hypertrophy and ultimately the regression from hypertrophy to failure.