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.
| Dai, Tieying; Tian, Ye; Tocchetti, Carlo Gabriele et al. (2007) Nitroxyl increases force development in rat cardiac muscle. J Physiol 580:951-60 |
| Dai, Tieying; Ramirez-Correa, Genaro; Gao, Wei Dong (2006) Apelin increases contractility in failing cardiac muscle. Eur J Pharmacol 553:222-8 |
| Stull, Linda B; Hiranandani, Nitisha; Kelley, Missy A et al. (2006) Murine strain differences in contractile function are temperature- and frequency-dependent. Pflugers Arch 452:140-5 |
| Gao, Wei Dong; Dai, Tieying; Nyhan, Daniel (2006) Increased cross-bridge cycling rate in stunned myocardium. Am J Physiol Heart Circ Physiol 290:H886-93 |
| Naumova, Anna V; Chacko, Vadappuram P; Ouwerkerk, Ronald et al. (2006) Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts. Am J Physiol Heart Circ Physiol 290:H837-43 |
| Janssen, Paul M L; Stull, Linda B; Leppo, Michelle K et al. (2003) Selective contractile dysfunction of left, not right, ventricular myocardium in the SHHF rat. Am J Physiol Heart Circ Physiol 284:H772-8 |
| Kogler, Harald; Fraser, Heather; McCune, Sylvia et al. (2003) Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium. Cardiovasc Res 59:582-92 |
| Stull, Linda B; Leppo, Michelle K; Marban, Eduardo et al. (2002) Physiological determinants of contractile force generation and calcium handling in mouse myocardium. J Mol Cell Cardiol 34:1367-76 |
| Janssen, Paul M L; Stull, Linda B; Marban, Eduardo (2002) Myofilament properties comprise the rate-limiting step for cardiac relaxation at body temperature in the rat. Am J Physiol Heart Circ Physiol 282:H499-507 |
| Kogler, H; Soergel, D G; Murphy, A M et al. (2001) Maintained contractile reserve in a transgenic mouse model of myocardial stunning. Am J Physiol Heart Circ Physiol 280:H2623-30 |
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