Pressure overload-induced cardiac hypertrophy is one of the most common causes of heart failure. Many intracellular signal transduction pathways have been implicated in the development of cardiac hypertrophy and the progression of hypertrophy to heart failure, among which the protein kinase C (PKC) signaling pathway is the focus of this proposal. In preliminary studies, we found that 1) a PKC binding protein, PICOT (PKC-lnteracting Cousin Of Thioredoxin), is up-regulated during the development of cardiac hypertrophy and 2) enforced expression of PICOT in the neonatal rat ventricular myocyte (NRVM) and rat hearts abrogates the development of cardiac hypertrophy. These results suggest that PICOT is a key negative feedback regulator of cardiac hypertrophy, and thus provides a novel strategy to block the development of cardiac hypertrophy and heart failure. The goal of this proposal is to define the molecular mechanism of PKC inhibition by PICOT, and to evaluate the beneficial effects of PICOT overexpression in the rodent models of cardiac hypertrophy and heart failure. We propose the following specific aims: 1) Defining the molecular mechanism of PICOT activity and its interactions with other PKC isoforms, 2) Characterizing the PICOT complex by proteomic approaches, and 3) Defining the physiological consequences of PICOT overexpression in the hearts in vivo. Accomplishing these three specific aims will provide a greater understanding of the negative feedback mechanism of cardiac hypertrophy exerted by inhibiting PKC activity, and will allow for the design of novel therapeutic strategies for the management of cardiac hypertrophy and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Evans, Frank
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Aguettaz, E; Lopez, J J; Krzesiak, A et al. (2016) Axial stretch-dependent cation entry in dystrophic cardiomyopathy: Involvement of several TRPs channels. Cell Calcium 59:145-55
Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind et al. (2015) Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy. Biochim Biophys Acta 1853:2870-84
Ishikawa, Kiyotake; Aguero, Jaume; Tilemann, Lisa et al. (2014) Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions. Am J Physiol Heart Circ Physiol 307:H1478-86
Fish, Kenneth M; Ladage, Dennis; Kawase, Yoshiaki et al. (2013) AAV9.I-1c delivered via direct coronary infusion in a porcine model of heart failure improves contractility and mitigates adverse remodeling. Circ Heart Fail 6:310-7
Chemaly, Elie R; Hajjar, Roger J; Lipskaia, Larissa (2013) Molecular targets of current and prospective heart failure therapies. Heart 99:992-1003
Lompré, A-M; Hadri, L; Merlet, E et al. (2013) Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy. Gene Ther 20:901-12
Lipskaia, Larissa; Hadri, Lahouaria; Lopez, Jose J et al. (2013) Benefit of SERCA2a gene transfer to vascular endothelial and smooth muscle cells: a new aspect in therapy of cardiovascular diseases. Curr Vasc Pharmacol 11:465-79
Arias, Teresa; Chen, Jiqiu; Fayad, Zahi A et al. (2013) Comparison of echocardiographic measurements of left ventricular volumes to full volume magnetic resonance imaging in normal and diseased rats. J Am Soc Echocardiogr 26:910-8
Lipskaia, L; Hadri, L; Le Prince, P et al. (2013) SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery. Gene Ther 20:396-406
Chen, Jiqiu; Petrov, Artiom; Yaniz-Galende, Elisa et al. (2013) The impact of pressure overload on coronary vascular changes following myocardial infarction in rats. Am J Physiol Heart Circ Physiol 304:H719-28

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