Michael T. Piascik, Ph.D.
Professor,
The Ohio State University, 1978.
Office: HSRB-150 Health Sciences Research Building (0305)
Lab: HSRB-148; (859) 323-8575
Tel: (859) 323-5107
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Research Interests
My research interests are in the regulation of cardiovascular function by the alpha1-adrenergic receptor subtypes. These studies were funded by grants from the National Heart, Lung and Blood Institute and the American Heart Association from 1980 through 2007. Alpha1-adrenergic receptors are members of the super family of G-protein coupled receptors. Currently there are 3 known subtypes of the alpha1-AR: the alpha1A, the alpha1B and the alpha1D. While working with Drs. Robert Graham and Dianne Perez, Dr. Piascik participated in the cloning and characterization of the alpha1A and the alpha1D-AR subtypes. Research techniques used in the lab are whole animal cardiovascular measurements in both rats and genetically altered mice, in vitro assessment of contractile function, measurement of growth responses, measurement of reactive oxygen species, immunocytochemistry and laser scanning confocal microscopy. In previous years we have focused on the regulation of peripheral vascular function by the alpha1-ARs subtypes. It is our hypothesis that, while all blood vessels express all receptors, a single receptor participates in contractile regulation. Furthermore, this regulatory receptor is different in different vascular beds. We believe that the alpha1A and the alpha1D-ARs are primarily involved in the regulation of vascular smooth muscle contraction. We believe that the major regulatory activity of the alpha1B-AR is in the regulation of hypertrophic growth responses. In our most recent studies, we have examined the role 0f the alpha1D-AR in the generation of reactive oxygen species. We also obtained evidence of a heretofore unrecognized linkage between this receptor and the tumor suppressor protein p53. Activation of the alpha1D-AR associated with human aortic smooth muscle cells resulted in a dose and time-dependent increase in the levels of mitochondrial reactive oxygen species (ROS). Prolonged alpha1D-AR activation resulted in smooth muscle cell apoptosis. Both the increase in ROS and apoptotic cell death were blocked by the non selective alpha1-AR antagonist prazosin as well as the selective alpha1D-AR antagonist BMY 7378. Increases in ROS and apoptosis were also blocked by the p38 MAP kinase inhibitor SB 202190 and the NAPDH oxidase inhibitor apocynin. The ERK1/2 inhibitor PD 98059 or the JNK inhibitor SP 600125 were without effect on increases in ROS levels or apoptosis. Pifithrin alpha, an inhibitor of the tumor suppressor protein p53, had no effect on ROS generation but did block -induced alpha1D-AR apoptosis. These data show that the alpha1D-AR is coupled to the generation of mitochondrial ROS by a pathway involving p38 and NADPH oxidase. These data provide evidence that the alpha1D-AR engages a pathway that ultimately results in p53 executed cell death. We also provide details of the pathway emanating from receptor activation to apoptosis. Agonist mediated stimulation of the alpha1D-AR leads to increases in mitochondrial ROS in a pathway that involved p38 MAP kinase and NADPH oxidase. The increase in ROS promotes the translocation of p53 to the mitochondria. Once assuming a mitochondrial location, p53 activates the mitochondrial cell death program resulting in vascular smooth muscle apoptosis.
Cole, M.P., Chaiswing, L., Oberley, T.D., Edelmann, S.E., Piascik, M.T., Lin, S-M, Kiningham, K.K. and St. Clair, D.
The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity.
Cardiovascular Research. 69: 186-197, 2006.
Garcia-Cazarin, M.L., Smith, J.L., McCune, D.F., Simmerman, L.A., Hadley, R., Kraner, S.D. and Piascik, M.T.
The alpha1D-adrenergic receptor is expressed intracellularly and coupled to increases in intracellular calcium and reactive oxygen species in human aortic smooth muscle cells.
Cell Signaling. 3: 6 2008.
Garcia-Cazarin, M.L., Smith, J.L., St. Clair, D. and Piascik, M.T.
The role of the tumor suppressor p53 in alpha1D-adrenergic receptor-induced apoptosis in vascular smooth muscle cells.
In press, Mol. Pharmacol. 74: 1000 - 1007, 2008
The 2008 papers probably represent the final publications from my laboratory. In the future, I will concentrate on teaching pharmacology to medical, dental and graduate students. Please take a few moments to examine these lecture materials.
Other Recent Publications
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Chalothorn D, McCune DF, Edelmann SE, Tobita K, Keller BB, Lasley RD, Perez DM, Tanoue A, Tsujimoto G, Post GR and Piascik MT. (2003)
"Differential cardiovascular regulatory activities of the alpha 1B- and alpha 1D-adrenoceptor subtypes."
J Pharmacol Exp Ther. 305:1045-53.
Yun J, Zuscik MJ, Gonzalez-Cabrera P, McCune DF, Ross SA, Gaivin R, Piascik MT and Perez DM. (2003)
"Gene expression profiling of alpha(1b)-adrenergic receptor-induced cardiac hypertrophy by oligonucleotide arrays."
Cardiovasc Res. 57:443-55.
Chalothorn D, McCune DF, Edelmann SE, Garcia-Cazarin ML, Tsujimoto G and Piascik MT. (2002)
Differences in the Cellular Localization and Agonist-Mediated Internalization Properties of the alpha(1)-Adrenoceptor Subtypes.
Mol Pharmacol 61:1008-16.
Waldrop, B.A., Piascik, M.T. and Post, G.R. (2002)
Regulation of cell growth and MAPK family members ERK, JNK, and p38 kinase by the Alpha-1B and Alpha-1D adrenergic receptor subtypes.
J Pharmacol Expt Ther 300:83-90.
Piascik, M.T. and Perez, D.M. (2001)
Perspectives in a1-adrenergic receptors: Pharmacology, Function and Future Directions., Invited Review, Perspectives in Pharmacology,
J Pharmacol Expt Ther 298:403-410.
Zuscik, M.J., Chalothorn, D., Hellard, D., Deighan, C. McGee, A., Daly, C.J., Waugh, D.J.J., Ross, S.A., Gaivin, R.J., Morehead, A.J., Thomas, J.D., Plow,
E.F., McGrath, J.C., Piascik, M.T., and Perez, D.M. (2001)
Hypotension, autonomic failure, and cardiac hypertrophy in transgenic mice over-expressing the alpha1B-adrenergic receptor.
J Biol Chem 276:13738-13743.
McCune DF, Edelmann SE, Olges JR, Post GR, Waldrop BA, Waugh DJJ, Perez DM and Piascik MT. (2000)
Regulation of the Cellular Localization and Signaling Properties of the alphaB- and alpha1D- Adrenoceptors by Agonists and Inverse Agonists.
Mol Pharmacol 57: 659-666.
Hrometz SL, Edelmann SE, McCune DF, Olges JR, Hadley RW, Perez DM and Piascik MT. (1999)
Expression of Multiple alpha1-Adrenoceptors on Vascular Smooth Muscle: Correlation with the Regulation of Contraction.
J Pharmacol Exp Ther 290: 452-463.
Porter JE, Edelmann S, Waugh DJ, Piascik MT and Perez DM. (1998)
The agonism and synergistic potentiation of weak partial agonists by triethylamine in alpha1 adrenergic receptor activation: Evidence for a salt-bridge as
the initiating process.
Mol Pharmacol 53:766-771.
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