Myofilament Function in Human Heart Failure

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): The central hypothesis that underlies this project is that the progressive decline in cardiac function seen in patients with non-ischemic heart failure is a reflection of the post-translational modification of cardiac contractile proteins, specifically the thin filaments proteins, troponin I, T and the regulatory myosin light chain (MLC2). To test this hypothesis, we will collect myocardial samples from two distinct groups: i) patients with and without diabetes undergoing coronary bypass surgery, ii) patients with idopathic dilated cardiomyopathy undergoing cardiac surgery (either ventricular modification or tranplantation) and, as controls patients with normal ventricular function undergoing valve replacement or bypass surgery. We will test the extent of myofilament dysfunction in skinned cells and determine whether dephosphorylation by PP1A will eliminate differences between sample groups (aim 1). Next, we will correlate myofilament function and clinical status with contractile protein isoform distribution and phosphorylation status, paying particular attention to the components of the troponin complex and the regulatory myosin light chain (aim 2). Finally, sarcomeric proteins will be extracted in the context of the pathologic cell and replaced with recombinant proteins that have been modified so as to recapitulate the non-pathologic situation (aim 3). The overall goal of the project is to identify specific and modifiable biochemical interfaces that might allow rational treatment of nonischemic cardiac muscle dysfunction.