Dr. Conklin
Daniel Conklin, Ph.D.
Associate Professor of Medicine
Tel.: (502) 852-5836
E-mail: dj.conklin@louisville.edu
RESEARCH INTERESTS
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.
PUBLICATIONS (last 5 years)
1. Dugas, T.R., M. F. Kanz, V.Y. Hebert, K.L. Hennard, H. Liu, V. Santa Cruz, D.J. Conklin and P.J. Boor. 2004. Vascular medial hyperplasia following chronic, intermittent exposure to 4, 4’-methylenedianiline. Cardiovasc. Toxicol.. 4(1):85-96.
2. Conklin, D.J., H.R. Cowley, R.J. Wiechmann, G.H. Johnson, M.B. Trent and P.J. Boor. 2004. Vasoactive effects of methylamine in isolated human blood vessels: Role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide. Am. J. Physiol. Heart Circ. Phys. 286:H667-H676.
3. Awe, S.O., A.S.O. Adeagbo, S.E. D’Souza, A. Bhatnagar and D.J. Conklin. 2006. Acrolein induces vasodilatation of rodent mesenteric bed via an EDHF-dependent mechanism. Toxicol. Appl. Pharm. 217(3):266-76.
4. Conklin, D.J., A. Bhatnagar, H. Cowley, G.H. Johnson, R.J. Wiechmann, L.M. Sayre, M.B. Trent and P.J. Boor. 2006. Acrolein stimulates hypercontraction in isolated human blood vessels. Toxicol. Appl. Pharm. 217(3):277-88.
5. Amunom, I., L.J. Stephens, V. Tamasi, J. Cai, W.M. Pierce, Jr., D.J. Conklin, A. Bhatnagar, S. Srivastiva, M.V. Martin, F.P. Guengerich and R.A. Prough. 2007. Cytochromes P450 catalyze oxidation of α, ß-unsaturated aldehydes. Arch. Biochem. Biophys. 464(2):187-96.
6. Arteel, G.A., L. Guo, T. Schlierf, J.I. Beier, J. P. Kaiser, T.S. Chen, M. Liu, D.J. Conklin, H.L. Miller, C. von Montfort and J.C. States. 2008. Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice. Toxicol. Appl. Pharm. 226(2):128-39.
7. West, M.B., G. Rokosh, D. Obal, M. Velayutham, Y-T. Xuan, B.G. Hill, R. Keith, J. Schrader, Y. Guo, D.J. Conklin, S.D. Prabhu, J.L. Zweier, R. Bolli and A. Bhatnagar. 2008. Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition. Circ. 118(19):1970-8.
8. Conklin, D.J., H.B. Lillywhite, B. Bishop, A.R. Hargens and K.R. Olson. 2009. Rhythmic contractility in the hepatic portal “corkscrew” vein of the rat snake. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 152(3):389-97.
9. O'Toole, T.E., Y-T. Zheng, J. Hellmann, D.J. Conklin, O. Barski, and A. Bhatnagar. 2009. Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages. Toxicol. Appl. Pharm. 236(2):194-201.
10. Conklin, D.J., P. Haberzettl, R.A. Prough and A. Bhatnagar. 2009. Glutathione S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. Am. J. Physiol. Heart Circ. Phys. 296(5):H1586-97.
11. Ng, S.P., D.J. Conklin, A. Bhatnagar, D. Bolanowski, J. Lyon and J.T. Zelikoff. 2009. Prenatal exposure to cigarette smoke induces diet- and gender-dependent dyslipidemia and weight gain in adult murine offspring. Environ. Health Pers. 117(7):1042-1048.
12. Baba S.P., O.A. Barski, Y. Ahmed, T.E. O'Toole, D.J. Conklin, A. Bhatnagar, and S. Srivastava. 2009. Reductive metabolism of AGE precursors: A metabolic route for preventing AGE accumulation in cardiovascular tissues. Diabetes. 58(11):2486-97.
13. Conklin, D.J., P. Haberzettl, J-F. Lesgards, R.A. Prough, S. Srivastava and A. Bhatnagar. 2009. Increased sensitivity of glutathione S-transferase P-null mice to cyclophosphamide-induced urinary bladder toxicity. J. Pharmacol. Exp. Ther. 331(2):456-69.
14. Campen M.J., Lund A.K., Knuckles T.L., Conklin D.J., Bishop B., Young D., Sielkop S.K., Seagrave J.C., Reed M.D., and McDonald J.D. 2009. Inhaled Diesel Emissions Alter Atherosclerotic Plaque Composition in ApoE-(-/-) Mice. Toxicol. Appl. Pharm. (in press).
15. Conklin, D.J., Barski, O.A., Lesgards, J-F., Juvan, P., Rezen, T., Rozman, D., Prough, R.A., Vladykovskaya, E., Liu, SQ., Srivastava, S. and Bhatnagar, A. 2009. Acrolein Consumption Induces Systemic Dyslipidemia and Lipoprotein Modification. Toxicol. Appl. Pharm. (in press).
* Highlighted articles represent grant-funded original observations.
