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Margaret Westfall

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Primary Appointment: Cardiac Surgery
Primary PIBS Dept.: Molecular and Integrative Physiology
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  The protein kinase C signaling pathway is an important modulator of cardiac contractile function and some PKC isoforms are significantly up-regulated during heart failure. Multiple neurohormones activate PKC in the heart, including alpha-adrenergic agonists, endothelin, and angiotensin II. A key PKC phosphorylation target is the troponin I isoform, located in the thin filament of the cardiac sarcomere. Troponin regulates Ca2+-activated contraction in striated muscle. The inhibitory troponin subunit, troponin I (TnI), plays a critical role as a molecular switch during Ca2+-activated muscle contraction and biochemical studies suggest phosphorylation of troponin I significantly modulates sarcomere force generation.

Activated PKC phosphorylates 5 amino acid residues located in 3 clusters on TnI. One focus of my laboratory is to determine the contribution of each cluster to PKC-mediated changes in contractile and relaxation in intact cardiac myocytes. Advances in molecular biology and viral-mediated gene delivery now allow us to exchange endogenous TnI with TnI containing substitutions at sites phosphorylated by PKC in adult cardiac myocytes. Recent results from our laboratory demonstrated PKC-mediated TnI phosphorylation plays an important role during relaxation, and is necessary to prevent diastolic dysfunction within cardiac myocytes. We also demonstrated a significant role for the Thr144 residue in the initial response to PKC activation by endothelin, while the Ser23/24 cluster contributes to relaxation with more prolonged PKC activation. Our current studies are focused on the role played by Ser43/45, which is the third phosphorylation cluster.

TnI phosphorylation may also play an important role under pathophysiological conditions. Earlier investigators report both increases and decreases in TnI phosphorylation during the development of heart failure. Thus, a second focus of my laboratory is investigating changes in PKC-mediated TnI phosphorylation during the development of heart failure using both animal models and failing human hearts. These studies also include proteomic analysis of large scale changes in protein expression as well as changes within the PKC signaling pathway in failing hearts.