Congestive heart failure is a major cause of death worldwide with as many as 50 percent of affected patients dying suddenly. At the cellular level, reduction of the calcium-independent transient outward current (Ito1) and prolongation of the action potential duration (APD) are consistently observed in experimental animal models of cardiac hypertrophy and failure and human heart failure. In hypertrophied myocytes Ito1 ) is decreased secondary to reductions in the expression of Kv4.2 and Kv4.3 potassium channel genes and more recently to the Kv 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 Ito1 and the potassium channel interacting protein. We propose the hypotheses 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 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 KChlP2 into aortic-banded rat hearts, diseased and normal human heart tissues, and into a swine model of pacing-induced heart failure. We will measure electrophysiological and Ca 2+ and enzyme activities and use rodent and large animal models to determine the effects of 1) Kv channel and KChlP manipulation on Itol and APD in vitro and in vivo and 2) the stress 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 progression from hypertrophy to failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Wang, Lan-Hsiang
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Massachusetts General Hospital
United States
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