Aruni Bhatnagar, PhD
Professor of Medicine, University Scholar
Tel.: (502) 852-5966/sec. 5724
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.
- Bhatnagar A, Srivastava SK, Szabo G. Oxidative stress alters specific membrane currents in isolated cardiac myocytes. Circ Res. 1990 Sep;67(3):535-49.
- Bhatnagar A. Electrophysiological effects of 4-hydroxynonenal, an aldehydic product of lipid peroxidation, on isolated rat ventricular myocytes. Circ Res. 1995 Feb;76(2):293-304.
- Srivastava S, Chandra A, Wang LF, Seifert WE Jr, DaGue BB, Ansari NH, Srivastava SK, Bhatnagar A. Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in isolated perfused rat heart. J Biol Chem. 1998 May 1;273(18):10893-900.
- Shinmura K, Tang XL, Wang Y, Xuan YT, Liu SQ, Takano H, Bhatnagar A, Bolli R. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10197-202.
- Tsakadze NL, Srivastava S, Awe SO, Adeagbo AS, Bhatnagar A, D'Souza SE. Acrolein-induced vasomotor responses of rat aorta. Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H727-34. Epub 2003 May 1.
- Bhatnagar A. Environmental cardiology: studying mechanistic links between pollution and heart disease. Circ Res. 2006 Sep 29;99(7):692-705.
- Luo J, Hill BG, Gu Y, Cai J, Srivastava S, Bhatnagar A, Prabhu SD. Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure. Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3673-84. Epub 2007 Oct 5.
- Wang GW, Guo Y, Vondriska TM, Zhang J, Zhang S, Tsai LL, Zong NC, Bolli R, Bhatnagar A, Prabhu SD. Acrolein consumption exacerbates myocardial ischemic injury and blocks nitric oxide-induced PKCepsilon signaling and cardioprotection. J Mol Cell Cardiol. 2008 Jun;44(6):1016-22. doi: 10.1016/j.yjmcc.2008.03.020. Epub 2008 Apr 8.
- Conklin DJ, Haberzettl P, Prough RA, Bhatnagar A. Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1586-97. doi: 10.1152/ajpheart.00867.2008. Epub 2009 Mar 6.
- Conklin DJ, Barski OA, Lesgards JF, Juvan P, Rezen T, Rozman D, Prough RA, Vladykovskaya E, Liu S, Srivastava S, Bhatnagar A. Acrolein consumption induces systemic dyslipidemia and lipoprotein modification. Toxicol Appl Pharmacol. 2010 Feb 15;243(1):1-12. doi: 10.1016/j.taap.2009.12.010. Epub 2009 Dec 23.
- Brook RD, Rajagopalan S, Pope CA 3rd, Brook JR, Bhatnagar A, Diez-Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC Jr, Whitsel L, Kaufman JD; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation. 2010 Jun 1;121(21):2331-78. doi: 10.1161/CIR.0b013e3181dbece1. Epub 2010 May 10.
- O'Toole TE, Hellmann J, Wheat L, Haberzettl P, Lee J, Conklin DJ, Bhatnagar A, Pope CA 3rd. Episodic exposure to fine particulate air pollution decreases circulating levels of endothelial progenitor cells. Circ Res. 2010 Jul 23;107(2):200-3. doi: 10.1161/CIRCRESAHA.110.222679. Epub 2010 Jul 1.
- Wheat LA, Haberzettl P, Hellmann J, Baba SP, Bertke M, Lee J, McCracken J, O'Toole TE, Bhatnagar A, Conklin DJ. Acrolein inhalation prevents vascular endothelial growth factor-induced mobilization of Flk-1+/Sca-1+ cells in mice. Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1598-606. doi: 10.1161/ATVBAHA.111.227124. Epub 2011 Apr 28.
- Ismahil MA, Hamid T, Haberzettl P, Gu Y, Chandrasekar B, Srivastava S, Bhatnagar A, Prabhu SD Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2050-60. doi: 10.1152/ajpheart.00120.2011. Epub 2011 Sep 9.
- Haberzettl P, Lee J, Duggineni D, McCracken J, Bolanowski D, O'Toole TE, Bhatnagar A, Conklin DJ. Exposure to ambient air fine particulate matter prevents VEGF-induced mobilization of endothelial progenitor cells from the bone marrow. Environ Health Perspect. 2012 Jun;120(6):848-56. doi: 10.1289/ehp.1104206. Epub 2012 Mar 14.