November 2011 Researcher of the Month - Srinivasan Vedantham, PhD
My research focus in the Diabetes Research Program has been to understand the metabolic basis of glucose flux and its impact on diabetic atherogenesis. In this context, our work has led to the novel finding that the glucose metabolizing enzyme, Aldose Reductase (AR), the first and rate-limiting enzyme in the polyol pathway assumes a critical role in the pathogenesis of diabetic complications. In our quest for studying the impact of AR in diabetic atherosclerosis, we have embarked on studies investigating flux via AR in influencing atherosclerotic lesion formation.
We have shown that human AR expression in apoE-/- mice is atherogenic and that expression specifically in endothelial cells leads to more disease. We have further demonstrated that use of a competitive inhibitor of AR that reduces, but does not eliminate AR activity, reduces atherosclerosis both in vivo and in vitro. Studies to dissect the mechanisms by which AR promotes atherogenesis are presently undertaken and we have observed some exciting findings hitherto unknown in the AR biology. Further, I am involved in studies related to understanding the pathogenesis of AR and vascular dysfunction in aging.
1. Srinivasan Vedantham, Radha Ananthakrishnan, Rosa Rosario, Ira Goldberg, Ann Marie Schmidt, Ravichandran Ramasamy. Aldose reductase mediates VCAM1 Expression in Endothelial Cells (EC) via Egr1, Experimental Biology 2011, Washington, DC (April 9-13, 2011)
2. Mariane Abdillahi, Radha Ananthakrishnan, Linshan Shang, Srinivasan Vedantham, Zhengbin Zhu, Rosa Rosario, Hylde Zirpoli, Ravichandran Ramasamy. Aldose reductase, glycogen synthase kinase 3 beta (GSK3β), and autophagy in ischemic hearts, Society for Heart and Vascular Metabolism 2010, Kananaskis, Canada.
3. Srinivasan V, U Tatu, V Mohan and M Balasubramanyam. Protein O-Glycosylation at the cross road of ER stress and Insulin resistance in L6 Skeletal muscle cells, Joint Third AOHUPO and Fourth Structural Biology and Functional Genomics Conference, National University of Singapore, December 2006, Singapore.
4. Sandhya N, Srinivasan V, Tatu U, Mohan V and Balasubramanyam M, Association of Palmitate-induced changes in adiponectin secretory pattern with insulin resistance in 3T3-L1 adipocytes, Joint Third AOHUPO and Fourth Structural Biology and Functional Genomics Conference, National University of Singapore, December 2006, Singapore.
5. Srinivasan V, Balasubramanyam M, Sampathkumar R, Tatu U & Mohan V., Molecular cross-talk between Calcium fluxes and Endoplasmic Reticulum (ER) Stress markers during the induction of insulin resistance by Glucosamine in L6 muscle cells, ASPUM2006, University of Madras, June 2006, India.
6. Balasubramanyam M, Srinivasan V, Tatu U, Mohan V. Convergence of ER stress and Hexosamine Pathways in the pathogenesis of Insulin resistance in L6 skeletal muscle cells, 2006, Diabetes, Vol.55, Supplement 1, A563. (Presented at the 66th American Diabetes Association Scientific Sessions, Washington, DC)
7. Srinivasan V, Balasubramanyam M, Tatu U and Mohan V. Insulin Resistance at the cross road of ER stress and Hexosamine Biosynthetic Pathway in L6 Skeletal muscle cells treated with Glucosamine, Indo-Swedish workshop on Genomics and Proteomics of diabetes, April 2006, Chennai.
8. Srinivasan V, Balasubramanyam M, Sampathkumar R, Tatu U and Mohan V. Differential regulation of Ca2+ and Endoplasmic Reticulum (ER) Stress markers during induction of Insulin resistance by Glucosamine in L6 muscle cells, ADNAT 2006, CCMB, Hyderabad, February 2006.
- CSIR- Senior Research Fellowship, Government of India
- Australia-India Council Fellow, Garvan visiting student, Garvan Institute of Medical Research, St. Vincent’s Hospital
- Proficiency award for securing first rank in B.Sc. Biochemistry
1. Zeng S, Zhang QY, Huang J, Vedantham S, Rosario R, Ananthakrishnan R, Yan SY, Ramasamy R, Emond JC, Friedman RA , Schmidt AM. Opposing Roles of RAGE and Myd88 signaling in extensive liver resection. FASEB J. 2012 Feb; 26(2):882-93.
2. Vedantham S, Noh H, Ananthakrishnan R, Son N, Hallam K, Hu Y, Yu S, Shen X, Rosario R, Lu Y, Ravindranath T, Drosatos K, Huggins LA, Schmidt AM, Goldberg IJ, Ramasamy R. Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic apoE-/- Mice, Arterioscler Thromb Vasc Biol. 2011 Aug; 31(8):1805-13.
3. Hallam KM, Li Q, Ananthakrishnan R, Kalea A, Zou YS, Vedantham S, Schmidt AM, Yan SF, Ramasamy R. Aldose reductase and AGE-RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging rats. Aging Cell. 2010 Oct; 9(5):776-84.
4. Vedantham S, Tatu U, Mohan V, Balasubramanyam M. Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells. Mol Cell Biochem. 2009 Aug; 328(1-2):217-24.
5. Vedantham S, Sandhya N, Sampathkumar R, Farooq S, Mohan V, Balasubramanyam M. Glutamine fructose-6-phosphate amidotransferase (GFAT) gene expression and activity in patients with type 2 diabetes: inter-relationships with hyperglycaemia and oxidative stress. Clin Biochem. 2007 Sep; 40(13-14):952-7.
6. Sundar Rajan S, Vedantham S, Balasubramanyam M, and Tatu U. Endoplasmic Reticulum (ER) stress and Diabetes (Review article). Ind J Med Res., 125(3), March 2007, pp 411-424.
7. Srinivasan V, M Rajesh, KN Sulochana, C Indra and S Ramakrishnan. Amino acids differentially regulate insulin tyrosine kinase and phosphatidyl inositol-3-OH kinase activities in human monocytes exposed to high glucose concentration. Indian Journal of Biochemistry & Biophysics, 2005, 42, 13-18.
8. Indira CS, Sulochana KN, Rajesh M, Srinivasan V, Ramakrishnan S. Beneficial role of amino acids in mitigating cytoskeletal Actin glycation, and improving F-Actin content: A possible medical treatment for Diabetic Retinopathy. Glycoconjugate Journal, 2001, 18(4), 277-282.
My future research interest is to study how maternal blood and food-derived AGEs predispose to diabetes and other chronic metabolic diseases in infants and young children. Additionally I am also interested in understanding developmental programming of obesity and metabolic syndrome during the life course using both animal models and human subjects. These studies help to further understand the etiology and pathogenesis of diabetes and its complications and provide avenues for newer therapeutic strategies to prevent the disease.