Department of Biochemistry and Molecular Biology

Professor

Email Dr. Bhatnagar
Phone Number: 502-852-4883
Fax: 502-852-6222

Address: 319 Abraham Flexner Way, 109 CVRC
Louisville, KY 40202

Ph.D., 1986, University of Kanpur, India

Area of Interest:

The major focus of our research is to elucidate the mechanisms by which oxidative stress affects cardiovascular function. In particular, we are interested in the role of lipid peroxidation as a contributor to myocardial ischemic injury and atherosclerosis. Although lipid peroxidation generates several reactive intermediates and end products, lipid-derived unsaturated aldehydes are believed to be a major source of oxidative stress and these toxicants appear to be critical mediators of tissue injury due to lipid peroxidation. In order to understand how the cardiovascular tissues protect themselves from the toxic products of lipid peroxidation, we are currently investigating the biochemical mechanisms by which unsatuarated aldehydes are detoxified in the heart and blood vessels. We have learned that the enzymes - aldose reductase, glutathione S-transferases and aldehyde dehydrogenase are the major constituents of aldehyde metabolism in the heart, and vascular smooth muscle and endothelial cells, and that these enzymes function in tandem to protect cardiovascular tissues from the harmful effects of lipid peroxidation. Based on this understanding we are currently assessing in detail the role of aldose reductase and related aldo-keto reductases in the detoxification of lipid peroxidation products. We are investigating whether inhibition or upregulation of these enzymes affects the ability of the heart to withstand oxidative stress during ischemia and reperfusion. In a parallel series of experiments we are studying the role of aldose reductase in atherogenesis in an effort to ascertain whether changes in aldehyde metabolism alter plaque burden in atherosclerotic animals. We believe that this line of inquiry will lead to a better understanding of the mechanisms by which oxidative stress mediates or exacerbates cardiovascular disease, and how the untoward cardiovascular effects of lipid peroxidation could be prevented. In addition to the metabolism and detoxification of endogenous aldehydes, our research interests also include cardiovascular toxicity of environmental aldehydes. Several ubiquitous pollutants such as gasoline vapor, car exhaust, smoke, and smog contain significant amounts of reactive aldehydes. Similar aldehydes are also generated during the metabolism of pollutants such as butadiene, vinyl chloride and allylamine and cardiotoxic drugs such as cylcophosphamide and adriamycin. These aldehydes are related, in structure and toxicity, to those generated endogenously during lipid peoxidation. Thus, our work on the lipid peroxidation-derived aldehydes bears significance for understanding the cardiovascular effects of environmental aldehydes. To examine this rigorously, we have recently initiated a series of studies to test whether environmental exposure to aldehydes exacerbates atherosclerosis and induces myocardial dysfunction, and whether aldehyde exposure is a risk factor for the development of heart disease.

Selected Publications:

Ruef, J., Liu, S.-Q., Bode, C., Tocchi, M., Srivastava, S., Runge, M., and Bhatnagar, A. Involvement of aldose reductase in vascular smooth muscle cell growth and lesion formation after arterial injury. Arterio. Thromb. Vasc. Biol. 20, 1745-1752, 2000.

Dixit, B.L., Balendiran, G.K., Watowich, S.J., Srivastava, S., Ramana, K.V., Petrash, J.M. Bhatnagar, A., and Srivastava, S.K.  Kinetic and structural characterization of the glutathione binding site of aldose reductase. J. Biol. Chem. 275, 21587-21595, 2000.

Shinmura, K., Tang, X-L, Wang, Y., Xuan, Y-T, Liu, S-Q, Takano, H., Bhatnagar, A., and Bolli, R. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits.  Proc. Natl. Acad Sci. USA 97, 10197-10202, 2000.

Srivastava, S., Conklin, D.J., Boor, PJ, Liu, S.Q., Srivastava, S.K., and  Bhatnagar, A. Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein-derived aldehyde - 4-hydroxy trans-2-nonenal in vascular smooth muscle cells.  Atherosclerosis   18, 339-350, 2001.

Liu, S.Q., Jin, H., Zacharias, A., Srivastava, S., Bhatnagar, A. Binding of pyridine coenzymes to the ?-subunit of the voltage-sensitive potassium channel.  J. Biol. Chem. 276, 11812-11820, 2001.