CELLULAR MECHANISMS OF CARDIAC CONTRACTILE DYSFUNCTION

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (adapted from the applicant's description): Previous work by this investigator and others has demonstrated that the reversible contractile dysfunction which occurs with myocardial stunning arises from excitation contraction uncoupling at the level of contractile proteins due to an acquired lesion of the contractile machinery. The functional changes are associated with partial proteolytic degradation of troponin I (TnI), which cleaves 17 amino acid residues from the c-terminus of TnI (TnI1-193). In this competitive renewal, the PI will test the hypothesis that TnI degradation is responsible for the contractile dysfunction of stunning. In specific aim 1, the PI will characterize calcium cycling and myofilament function in transgenic mice overexpressing the degradation fragment TnI1-193, and in adult rabbit cardiac trabeculae and ventricular cells following introduction of TnI1-193 by viral gene transfer. In specific aim 2, the PI will determine the relative contribution of calcium cycling and the myofilaments to the contractile dysfunction in heart failure by investigating E-C coupling in failing SHHF rat myocardium as a function of stimulation frequency, and in SHHF rats at the premorbid hypertrophic and decompensated stages. Comprehensive analysis of contractile protein composition at the various stages of disease will be performed. In specific aim 3, the PI will determine the mechanisms by which xanthine oxidase inhibitors alter E-C coupling by testing whether its myofilament sensitizing effects are due to inhibition of superoxide or oxygen free radicals and to determine whether up-regulation of xanthine oxidase magnifies oxidant stress in heart failure contributing to myofilament dysfunction.