Dr.Prasanth Puthanveetil, Ph.D.

Cardiorenal diseases
Vascular complications
Diabetes and metabolic diseases

Major projects:

A . “Role of Synthetic Glucocorticoids in regulating cardiac metabolism”. This project comprises of 3 of my first authored articles and one second author peer reviewed original article which include;
1) Puthanveetil P, Wang F, Kewalramani G, Kim MS, Hosseini-Beheshti E, Ng N, Lau W, Pulinilkunnil T, Allard M, Abrahani A, Rodrigues B. Cardiac glycogen accumulation after dexamethasone is regulated by AMPK. Am. J. Physiol. 295:1753-1762, 2008.
2) Puthanveetil P, Wang Y, Wang F, Kim MS, Abrahani A, Rodrigues B. The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis. Endocrinology 151(5):2306-18, 2010.
3) Puthanveetil P, Rodrigues B. Glucocorticoid excess induces accumulation of cardiac glycogen and triglyceride through AMPK activation. Current Pharm Design (Invited review). 19(27):4818-30, 2013.
4) Girish Kewalramani, Prasanth Puthanveetil, Fang Wang, Min Suk Kim, Sylvia Deppe, Ashraf Abrahani, Dan S Luciani, James D Johnson, Brian Rodrigues. AMP-activated protein kinase confers protection against TNF-α-induced cardiac cell death. Cardiovascular research, 84 (1), 42-53, 2009.

Glucocorticoids are exogenously administered for chronic inflammatory illness like rheumatoid arthritis and asthma and endogenously released in excess following stress induced HPA axis activation and following abnormal pituitary and adrenal functions like tumors. These excess glucocorticoids in system have impact on various organs including cardiovascular system. In my research studies, I have tried to find out what role glucocorticoids have got in regulating cardiac metabolism. My research findings have shown that glucocorticoids by stimulating stress kinases like p38 MAPK, stimulate the nuclear entry and transactivation of FoxO1. An enhanced activation of FoxO1 results in induction of PDK4 mRNA and protein. The PDK4 protein is a rate limiting enzyme in glucose oxidation. PDK4 promotes phosphorylation dependent inactivation of pyruvate dehydrogenase complex which is known to promote glucose oxidation. Following glucocorticoid administration if there is a decreased glucose oxidation, all the entered glucose molecules goes to accumulate as glycogen. My study also showed that glucocorticoids increase GLUT4 mRNA and protein which is a major glucose transporter in the heart, thus confirming their role in enhanced glucose delivery to the heart. Thus glucocorticoids by down regulating glucose oxidation enhances fatty acid and ketone body utilization by the heart which is detrimental for the heart based on the metabolite byproducts formed from fats and also by accumulating entered glucose as glycogen excess, which is a glucose polymer, they can cause severe complications like hypertrophy and arrhythmias in the heart. My research using isolated cardiomyocytes and hearts isolated from rats have studied in detail the role of glucocorticoids in regulating cardiac metabolism. Thus by understanding the mechanisms by which glucocorticoids regulate metabolism we will able to understand and limit the cardiovascular complications associated with excess glucocorticoids.

B . “Role of FoxO1-iNOS signaling in Cardiac cell homeostasis during metabolic stress”. In this area, I have published three articles with me as the first authored work, which includes two peer reviewed original article and a review article. The publications include;
1. Puthanveetil P, Wan A and Rodrigues B. FoxO1 is Crucial for Sustaining Cardiomyocyte Metabolism and Cell Survival. Cardiovasc Res. 2013 Mar 1;97(3):393-403.
2. Puthanveetil P, Zhang D, Wang Y, Wang F, Abrahani A, Rodrigues B. Diabetes triggers a PARP1 mediated death pathway in the heart through the mediation of FoxO1. JMCC Nov;53(5):677-86, 2012.
3. Puthanveetil P, Wang Y, Zhang D, Wang F, Kim MS, Innis S, Pulinilkunnil T, Abrahani A, Rodrigues B. Cardiac triglyceride accumulation following acute lipid excess occurs through activation of a FoxO1-iNOS-CD36 pathway. Free Radic Biol Med. 51(2):352-63, 2011.

The earlier work was focused upon the role of FoxO1-iNOS signaling in enhancing membrane CD36 presence resulting in lipid entry and free radical generation in the cardiovascular tissue. Also this work describes the impact of activated FoxO1-iNOS signaling in downregulating mitochondrial oxidative proteins due to enhanced lipid uptake mediated lipotoxicity. It was accepted in one of the top journals in the field of free radical research and medicine, the Free Radical Biology and Medicine Journal (FRBM). Importantly, it is being recommended by Faculty of 1000 Prime as one of the significant work in understanding the role of FoxO1 and iNOS as a relevant therapeutic target for treating cardiovascular complications following lipid excess. The next work had shed light into the PARP1 induced cell death pathways, a process mediated by FoxO1-iNOS signaling. This work has compelled other researchers to think from a different and novel perspective, which is an apoptosis and necrosis independent cell death regulated by PARP1 and AIF, also termed as parthanatos. This was published in a good impact journal – Journal of Molecular and Cellular Cardiology (JMCC).
Based on these findings, I received an invitation to write a review article on FoxO1 and its role on cardiac homeostasis in a highly respected journal in the field of cardiovascular science – Cardiovascular Research.