 |
David J. Pinsky, M.D.
~J. Griswold Ruth M.D. & Margery Hopkins Ruth Professor of Internal
Medicine
~Professor of Molecular and Integrative Physiology
~Chief, Cardiovascular Medicine
~Scientific Director, Cardiovascular Center
1150 W. Medical Center Drive
MSRB III, 7220
Ann Arbor, MI 48109-0644
Phone: 734-936-3500
Fax: 734-936-8266
dpinsky@umich.edu
|
Current Research:
The predominant research focus is to elucidate the mechanisms by which blood vessels modulate their phenotype following periods of interrupted blood flow. Even relatively brief periods of ischemia trigger a dynamic alteration in the endovascular wall, leading to microvascular dysfunction consisting of inflammation, thrombosis, and edema. The signal transduction mechanisms leading to this cascade of pathological events are being elucidated at the molecular and cellular levels, with a focus on injury of vascular beds in the heart, lungs, and brain. A ?master switch? transcription factor, early growth response gene-1 (Egr-1) is activated by ischemia, which ignites pleiotropic inflammatory and thrombotic cascades. Direct suppression of Egr-1, or more indirect methods to reduce microvascular dysfunction (such as restoring deficient cyclic nucleotide second messenger pathways) can markedly attenuate ischemic vascular injury, which improves organ preservation and reduces allograft arteriopathy. Because nitric oxide (NO), a critical vascular homeostatic regulatory molecule, is rapidly quenched during reperfusion by reactive oxygen species, another diatomic biological gas (carbon monoxide, CO) subsumes a critical regulatory role in ischemic tissue. Paradoxically, inhaling minuscule amounts of this otherwise lethal gas can afford significant vascular protection during reperfusion. Efforts are underway to elucidate the signal transduction mechanisms by which endogenous and inhaled CO exert their homeostatic regulatory effects on injured blood vessels. In addition to cell culture paradigms of ischemia-reperfusion, various animal models are used in the laboratory to understand the pathophysiological consequences of ischemia-induced microvascular dysfunction. These include models of stroke, lung ischemia, and heart transplantation in gene-altered mice, as well as lung transplantation in rats. In the setting of stroke, microvascular thrombus accrues after the index ischemic event, and this can be suppressed (without increasing intracerebral hemorrhage) by targeted inhibition of intrinsic coagulation, or by metabolically deleting ADP from the platelet releasate. CD39, the prime endothelial ATP/ADP diphosphohydrolase, is under study as a critical thromboregulatory and leukoregulatory molecule in ischemic vascular beds. Ischemia-driven upregulation of other inflammatory mediators, such as integrin- or selectin-class adhesion receptors, or complement proteins represent related thematic areas under investigation. Ultimately, the goals of the laboratory are to develop new insights into endogenous mechanisms of ischemic vascular injury and protection, in order to develop new therapeutic strategies targeted at the intersection of thrombotic, fibrinolytic, and inflammatory axes.
Selected
Publications:
Ten VS, RI Stark, & DJ Pinsky: Neurofunctional assessment of sensorimotor deficit in a neonatal murine model of hypoxic-ischemic encephalopathy. Pediatr. Res. 51(4):361A, 2002.
H Liao, CY Wang, & DJ Pinsky: Carbon monoxide suppresses serpine-1 transcription and thereby attenuates prothrombotic effect of low ambient oxygen. Accepted for presentation at the American Heart Association Annual Scientific Sessions, November 2002.
Mazer SP, CW Towe, CF Liu, L Chess, & DJ Pinsky: Cognate Interaction between collagen IV and Very Late Antigen-1 (VLA-1) as a novel mechanism driving restenosis. Accepted for presentation at the American Heart Association Annual Scientific Sessions, November 2002.
Mazer SP, DJ Pinsky: Very late antigen-1 (VLA-1) expressed on neutrophils mediates their adhesion to sites of arterial injury and drives arterial restenosis. American Heart Association Scientific Sessions, November 2003.
Yoshikawa Y, DJ Pinsky: Downregulation of endothelial CD39 expression by hypoxic or ischemic stress. American Heart Association Scientific Sessions, November 2003.
Mazer SP, M Fedarau, Y-L Liu, DW Hwang, CW Towe, CF Liu, KE Olson, MJ Broekman, AJ Marcus, TA Deisher, DJ Pinsky: Deletion of endothelial ectoapyrase (CD39) promotes atherogenesis in hyperlipidemic mice. American Heart Association Scientific Sessions, November 2004.
Harada H, Y Yoshikawa, V Lama, H Liao, D Bouis, E Filippova, K Iwanaga, S Yanamadala, M Fedarau, C Ruwende, DJ Pinsky. Zinc finger transcription factor early growth response gene-1 (Egr-1) pPromotes development of obliterative airway disease in murine allografts. American Heart Association Scientific Sessions, November 2004.
Back to list of faculty
|
