Daniel Conklin, PhD
Associate Professor of Medicine
Tel.: (502) 852-5836
Recent epidemiological studies reveal that cardiovascular disease and diabetes are antagonized by environmental pollutant exposure. The presence of aldehydes in complex air borne mixtures of particulate matter (e.g., smog, tobacco smoke, automobile exhaust, etc) is well-documented but the contribution these aldehydes play in causing or exacerbating cardiovascular disease is unknown. Additional sources of environmental aldehydes include foods and beverages. Moreover, environmental aldehydes can induce formation of endogenous aldehydes via oxidative stress and lipid peroxidation, as well as by stimulating inflammatory processes that involve myeloperoxidase-mediated actions. An additional source of endogenous aldehyde exposure is the metabolism of exogenous and endogenous compounds, such as allylamine, cyclophosphamide, and polyamines, within cardiovascular and systemic tissues, which generate a particularly reactive aldehyde -- acrolein. We have focused on acrolein action in cardiovascular tissues over the past 10 years, and our studies show that acrolein is a powerful cardiovascular toxin that can induce dyslipidemia, block cardiac preconditioning, enhance thrombus formation, stimulate blood vessel hypercontraction and endothelial dysfunction, and elicit endothelial-dependent relaxation via NO- and EDHF-dependent pathways. Future studies will focus on uncovering the mechanisms of action of acrolein-induced cardiovascular toxicity for developing intervention strategies.
Because metabolism of aldehydes, such as acrolein, is a likely important determinant of acrolein tissue concentration and action we have probed the role of aldehyde metabolizing enzymes as a way to understand the nature of aldehyde-induced cardiotoxicity. Recent studies demonstrate that tissue deficiency of the acrolein-metabolizing enzyme, glutathione-S-transferase (GST), affects the sensitivity of the cardiovascular tissues and extra-cardiac structures, including urinary bladder. These data could help explain how many GST polymorphisms, which are present in human populations, increase the relative risk for cardiovascular disease in those individuals exposed to high levels of air pollution. Collectively, human epidemiological studies and our experimental models serve as notice of the potentially dramatic cardiovascular responses elicited by aldehyde exposure, especially in tissues with altered levels of aldehyde metabolizing enzymes, including the GSTs. Subsequent studies will focus on how GST deficiency increases cardiovascular sensitivity to air pollution and aldehydes.
- Salabei JK, Conklin DJ. Cardiovascular Autophagy: Crossroads of Pathology, Pharmacology and Toxicology. Cardiovasc Toxicol. 2013 Feb 14. [Epub ahead of print]
- Conklin DJ. From lung to liver: how does airborne particulate matter trigger NASH and systemic insulin resistance? J Hepatol. 2013 Jan;58(1):8-10. doi: 10.1016/j.jhep.2012.10.008. Epub 2012 Oct 13.
- Obal D, Dai S, Keith R, Dimova N, Kingery J, Zheng YT, Zweier J, Velayutham M, Prabhu SD, Li Q, Conklin D, Yang D, Bhatnagar A, Bolli R, Rokosh G. Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion. Basic Res Cardiol. 2012;107(6):305. doi: 10.1007/s00395-012-0305-1. Epub 2012 Oct 26.
- Salabei JK, Balakumaran A, Frey JC, Boor PJ, Treinen-Moslen M, Conklin DJ. Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy. Toxicol Appl Pharmacol. 2012 Aug 1;262(3):265-72. doi: 10.1016/j.taap.2012.04.036. Epub 2012 May 22.
- 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.
- Conklin DJ, Bhatnagar A. Are glutathione S-transferase null genotypes "null and void" of risk for ischemic vascular disease? Circ Cardiovasc Genet. 2011 Aug 1;4(4):339-41. doi: 10.1161/CIRCGENETICS.111.960526.
- Conklin DJ, Prough RA, Juvan P, Rezen T, Rozman D, Haberzettl P, Srivastava S, Bhatnagar A. Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase. Mol Nutr Food Res. 2011 Sep;55(9):1411-22. doi: 10.1002/mnfr.201100225. Epub 2011 Aug 3.
- 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.
- Conklin DJ. Beware the air! Why particulate matter matters. Circ Res. 2011 Mar 18;108(6):644-7.
- Wetzelberger K, Baba SP, Thirunavukkarasu M, Ho YS, Maulik N, Barski OA, Conklin DJ, Bhatnagar A. Postischemic deactivation of cardiac aldose reductase: role of glutathione S-transferase P and glutaredoxin in regeneration of reduced thiols from sulfenic acids. J Biol Chem. 2010 Aug 20;285(34):26135-48. Epub 2010 Jun 10.
- Conklin DJ, Haberzettl P, Lesgards JF, Prough RA, Srivastava S, Bhatnagar A. Increased sensitivity of glutathione S-transferase P-null mice to cyclophosphamide-induced urinary bladder toxicity. J Pharmacol Exp Ther. 2009 Nov;331(2):456-69. doi: 10.1124/jpet.109.156513. Epub 2009 Aug 20.
- Ng SP, Conklin DJ, Bhatnagar A, Bolanowski DD, Lyon J, Zelikoff JT. Prenatal exposure to cigarette smoke induces diet- and sex-dependent dyslipidemia and weight gain in adult murine offspring. Environ Health Perspect. 2009 Jul;117(7):1042-8. doi: 10.1289/ehp.0800193. Epub 2009 Apr 13.
- 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.