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 Gazes Cardiac Research Institute | faculty | Dhandapani Kuppuswamy, Ph.D.

Dhandapani Kuppuswamy, Ph.D.

A major research interest in my laboratory is focused on protein kinase signaling in hypertrophying myocardium:

(i) Protein kinase signaling in hypertrophying myocardium:

      Hypertrophy is the basic adaptive response of the adult heart to hemodynamic overload such as pressure or volume overload. While the initial response to the increased demand of cardiac muscle function is compensated by the hypertrophic growth of the cardiac muscle cell, this functionality fails and results in congestive heart failure (CHF) when the load increase exceeds the growth capacity. Therefore, it is important to identify the intermediate pathways both during the initial compensatory hypertrophy and during the transition into decompensatory hypertrophy resulting in CHF. Our recent experiments in the initial phase of pressure overload-induced cardiac hypertrophy showed the presence of two major signaling pathways:

      (a) During an early period of pressure overload (1 to 4 hr), a signaling cascade that is independent of integrins, occurs with the activation of protein kinase C, c-Raf and p70/85S6K (S6K1). Since S6K1 is important for enhancing the translational capacity of the cell, we are studying the mechanism and role of PKC/c-Raf/MEK/ERK pathway in the activation of S6K1 and in the mobilization of ribosomal mRNA possessing polypyrimidine tract in the 5'-untranslated region (5'-TOP mRNA) into polysomes for protein translation.

     (b) During the later period of pressure overload (4 to 48 hr), an integrin-dependent signaling occurs that results in the cytoskeletal (CSK) assembly and activation of non-receptor tyrosine kinases (focal adhesion kinase (FAK and c-Src) and several adapter proteins (p130Cas, Nck and Shc). To determine the role of this assembly, we have developed a cell culture model in which integrin is activated with Arg-Gly-Asp (RGD) peptide after embedding adult cardiocytes in collagen gel. This model mimics most of our in vivo data on integrin activation and focal complex formation. We are exploring the importance of this activation with respect to hypertrophic growth (possibly for the sustained activation of S6K1) and survival of adult cardiocytes (by the activation of NFkB and STAT3 signaling pathways).

Dr Kuppuswamy's Lab
Laboratory Members
Dorea Pleasant,MS
Kamala Sundararaj,Ph.D

Sundar Balasubramanian, Ph.D

Publications

Pubmed Listing

1.     Kuppuswamy, D, Kerr, C, Narishige, T, Kasi, V.S, Menick, R, and Cooper, G, IV:  Association of tyrosine phosphorylated c-Src with the cytoskeleton of hypertrophying myocardium. J. Biol. Chem., 272, 4500-4508, 1997.

2.   Kasi, VS, and Kuppuswamy, D.: Inhibition of SRC family kinases by a combinatorial action of 5’AMP and small heat shock proteins, both identified from the adult heart. Mol. Cell. Biol., 19, 6858-6871, 1999.

3.  Laser, M, Willey, D, Jiang, W, Cooper, G IV, Menick, DR, Zile, RM, Kuppuswamy, D: Integrin activation and focal complex formation in cardiac hypertrophy. J Biol Chem, 275: 35624-3530, 2000.

4. Willey, CD, Balasubramanian, S, Rodriguez-Rosas, MD, Ross, RS, Kuppuswamy, D.:  Focal complex formation in adult cardiomyocytes is accompanied by the activation of β3 integrin and c-Src.  J Mol Cell Cardiol, 35: 671-683, 2003.

5.Balasubramanian S, and Kuppuswamy D:  RGD-containing peptides activate S6K1 through β3 integrin in adult cardiac muscle cells.  J Biol Chem, 278: 42214-42224, 2003.

6.Balasubramanian S, Mani S, Shiraishi H, Johnston RK, Yamane K, Willey CD, Cooper G IV, Tuxworth WJ, Kuppuswamy D: Enhanced ubiquitination of cytoskeletal proteins in pressure-overloaded myocardium is accompanied by changes in specific E3 ligases. J Mol Cell Cardiol, 41: 669-79, 2006.

7. Willey, CD, Palanisamy, A, Shiraishi, H, Balasubramanian, S, Zile, MR, Tuxworth, WJ, and Kuppuswamy, D.: STAT3 activation in pressure-overloaded feline myocardium: role for integrins and the tyrosine kinase BMX. International Journal of Biological Sciences, 27: 184-99, 2008.  PMCID: PMC2443357

8.Balasubramanian, S, Johnston, RK, Moschella, PC, Mani, SK, Tuxworth, SJ, and Kuppuswamy, D: mTOR in Growth and Protection of Hypertrophying Myocardium. Cardiovascular and Hematological Agents in Medicinal Chemistry, 7: 52-63, 2009. PMCID: In Progress.

9.Johnston, RK, Balasubramanian, S, Kasiganesan, H, Baicu, CF, Zile, MR, and Kuppuswamy, D:  integrin-mediated ubiquitination activates survival signaling during myocardial hypertrophy. FASEB J, 23: 2759-71, 2009. PMCID: PMC2717769.

10.Harston, RK, Kuppuswamy, D. Integirns are necessary links to hypertrophic growth in cardiomyocytes. J Signal Transduct. 2011;2011:521742. Epub 2011 Feb 21. PMCID:PMC3101892

Dhandapani Kuppuswamy, Ph.D.

Dhandapani Kuppuswamy, Ph.D.
Principal Investigator at the Gazes Cardiac Research Institute Associate
Professor of Medicine

Dr. Kuppuswamy's Contact Information

Room 237, Gazes/Thurmond Building
114 Doughty St.
Charleston, SC 29403

Phone: (843)876-5069
Lab:(843)876-5049
Fax:(843)876-5068
Email: Kuppusd@musc.edu

Dr. Kuppuswamy's Education
1975 B.S. Chemistry, Mathematics, Physics, University of Madras, India
1978 M.S. Biochemistry, University of Madras, India
1979 M.Phil. University of Madras, India
1984 Ph.D., Biochemistry, University of Madras
1981-82 Junior Research Fellow, Council of Scientific and Industrial Research, University of Madras, India
1982-84 Senior Research Fellow, Council of Scientific and Industrial Research, University of Madras, India
1984-86 Postdoctoral Fellow, Department of Biochemistry, Mount Sinai School of Medicine, New York, NY
1986-91 Research Associate, HHMI, Department of Biochemistry, Washington University School of Medicine, St. Louis, MO
1991-93 Research Instructor, Department of Biochemistry, Washington University School of Medicine, St. Louis, MO
1993-94 Research Trainee, Department of Pathology, University of North Carolina, Chapel Hill, NC