Aging has an enormous negative impact on the cerebral circulation. One of the primary mechanisms thought to underlie many of the major changes that occur with aging involves oxidative stress. The overall goal of this project is to define molecular mechanisms which protect the cerebral vasculature from oxidative stress and dysfunction during aging. Although cerebral vascular disease, stroke, and vascular dementia all increase markedly with age, almost nothing is known regarding the importance of oxidative stress in the cerebral circulation with aging. In preliminary data, we observed superoxide-mediated vascular dysfunction during aging that was of greater magnitude and occurred earlier in cerebral arteries than in the carotid artery or aorta.
Our first Aim i s to test the hypothesis that oxidative stress plays a major role in mediating this dysfunction. Peroxisome proliferator activated receptors (PPARs) are transcription factors that may produce antioxidant effects. The role of PPARy in the cerebral circulation is not known.
Our second Aim i s to examine the hypothesis that PPARy protects the cerebral vasculature under normal conditions and during aging. Using a mouse expressing a human dominant negative mutation in PPARy, a 'humanized'mouse, we have obtained preliminary evidence that PPARy exerts major protective effects in cerebral blood vessels. We will determine if oxidative stress contributes to impairment of vascular function in adult mice expressing this dominant negative form of PPARy. We will also determine if a synthetic activator of PPARy or genetic overexpression of wild-type PPARy in endothelium decreases oxidative stress and improves vascular function in aging. One mechanism by which oxidative stress may produce vascular dysfunction involves asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial NO synthase.
In Aim 3, we will use mice overexpressing the ADMA hydrolyzing enzyme, dimethylarginine dimethylaminohydrolase, to test the hypothesis that aging produces adverse vascular effects through an ADMA-dependent mechanism. Our preliminary data support these hypotheses. Because synthetic activators of PPARy are already approved for clinical use, this area of basic research has implications for translational medicine. Our focus on mechanisms of oxidative stress and endothelial dysfunction seems appropriate since endothelial dysfunction has a major impact on the vessel wall and has emerged as an independent predictor of clinical events. These studies should provide new insight into mechanisms of vascular protection during aging and fit well within several major themes of this program - cardiovascular risk factors, oxidative stress, and mechanisms of vascular protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS024621-25
Application #
8375546
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
25
Fiscal Year
2012
Total Cost
$323,434
Indirect Cost
$107,812
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Ketsawatsomkron, Pimonrat; Keen, Henry L; Davis, Deborah R et al. (2016) Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-? Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension. Hypertension 67:214-22
Dayal, Sanjana; Gu, Sean X; Hutchins, Ryan D et al. (2015) Deficiency of superoxide dismutase impairs protein C activation and enhances susceptibility to experimental thrombosis. Arterioscler Thromb Vasc Biol 35:1798-804
Rodionov, Roman N; Jarzebska, Natalia; Weiss, Norbert et al. (2014) AGXT2: a promiscuous aminotransferase. Trends Pharmacol Sci 35:575-82
De Silva, T Michael; Modrick, Mary L; Ketsawatsomkron, Pimonrat et al. (2014) Role of peroxisome proliferator-activated receptor-? in vascular muscle in the cerebral circulation. Hypertension 64:1088-93
Chrissobolis, Sophocles; Drummond, Grant R; Faraci, Frank M et al. (2014) Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation. J Hypertens 32:1815-21
Johnson, Andrew W; Kinzenbaw, Dale A; Modrick, Mary L et al. (2013) Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension. Hypertension 61:437-42
Chu, Yi; Lund, Donald D; Weiss, Robert M et al. (2013) Pioglitazone attenuates valvular calcification induced by hypercholesterolemia. Arterioscler Thromb Vasc Biol 33:523-32
Klykov, Corinne M; Lentz, Steven R (2013) Trends in clinical laboratory homocysteine testing from 1997 to 2010: the impact of evidence on clinical practice at a single institution. Clin Chem Lab Med 51:671-5
Dayal, Sanjana; Wilson, Katina M; Motto, David G et al. (2013) Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis. Circulation 127:1308-16
Miller, Jordan D; Chu, Yi; Castaneda, Lauren E et al. (2013) Vascular function during prolonged progression and regression of atherosclerosis in mice. Arterioscler Thromb Vasc Biol 33:459-65

Showing the most recent 10 out of 431 publications