Michael Ihnat
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EDUCATION
B.S., Pharmacy, Cum Laude with Honors and Distinction, The Ohio State University, Colombus, Ohio
Ph.D., Pharmacology and Toxiocology, Dartmouth Medical School, Hanover, New Hampshire
MEMBERSHIPS
Society of Toxicology
The Association for Research in Vision and Ophthalmology
The American Association for the Advancement of Science
American Diabetes Association
RESEARCH SUMMARY
Cellular response to chronic stresses. Research in our laboratory involves studying the response of retinal, endothelial, and smooth muscle cells and organs of intact rodents to chronic stresses (decreased oxygen, high glucose, environmental levels of arsenic). Our global hypothesis is that vascular stress signaling persists long after stressors are removed. Our current and future questions are to determine what biochemical mechanisms are driving this persistence of stress signaling, and how this persistence can be therapeutically interrupted using antioxidant drugs.
With respect to high glucose as a stressor, we have found that there is a cellular “memory� or persistence of high glucose stress signaling both in isolated cells and in the kidney and retina of diabetic rats. We have found that a general antioxidant food supplement, α-lipoic acid, currently in clinical trials was capable of disrupting this cellular “memory.� Finally, we have found that reactive species generated both in the mitochondria and the cytosol are contributing to this persistence phenomenon. Ongoing and future work is to determine the length of this persistence phenomenon, whether this “memory� is cell-specific, and whether α-lipoic acid can be used clinically to interrupt the cellular “memory� of high glucose stress signaling.
With respect to decreased oxygen as a stressor, like with high glucose, we have found that hypoxic stress signaling through a global hypoxia regulator called hypoxia inducible factor (HIF) persists in the vascular cells long after oxygen levels are normalized. Ongoing and future work is to determine the mechanism behind this HIF stress signaling persistence, and as with high glucose, to determine whether agents can be used to interrupt this persistence phenomenon.
Finally, we are applying a very common environmental toxicant, arsenite (As(III)), to this same scenario. For many years it has been known that As(III) has considerable deleterious effects on the vasculature. We are now interested as to whether diabetic patients exposed to low, environmentally-relevant levels of As(III) through their drinking water may have a more profound incidence and severity of vascular diabetic complications and what the biochemical mechanism behind of these effects might be.
SELECTED PUBLICATIONS
1. Ihnat, M.A., Thorpe, J.E., Kamat, C.D., Szabo, C., Green, D.E., Warnke, L.A., Lacza, Z., Cselenyák, A., Ross, K., Shakir, S., Piconi, L. and Ceriello, A. Role of Extra-Mitochondrial Reactive Species in a "Memory" of Vascular Stress Signaling Diabetologia, Accepted 3.15.07
2. Ihnat, M. A., Thorpe, J. E., and Ceriello, A. (2007). Hypothesis: the 'metabolic memory', the new challenge of diabetes. Diabet Med.
3. Kamat, C. D., Green, D. E., Warnke, L., Thorpe, J. E., Ceriello, A., and Ihnat, M. A. (2007). Mutant p53 facilitates pro-angiogenic, hyperproliferative phenotype in response to chronic relative hypoxia. Cancer Lett 249, 209-19.
4. Kamat, C. D., Thorpe, J. E., Shenoy, S. S., Ceriello, A., Green, D. E., Warnke, L. A., and Ihnat, M. A. (2007). A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization. BMC Cardiovasc Disord 7, 4.
5. Kamat, C.D., Green, D.E., Curilla, S., Warnke, L., Hamilton, J.W., Sturup, S., Clark,C. and Ihnat, M.A. Role of HIF signaling on tumorigenesis in response to chronic low dose arsenic administration, Toxicol Sci. 86:248-257 (2005)
MAILING ADDRESS
University of Oklahoma Health Sciences Center
Department of Cell Biology
P.O. Box 26901
Oklahoma City, Oklahoma 73126-0901
Phone: (405) 271-8001 ext. 47965
Fax: (405) 271-3548
