Superoxide and other reactive oxygen species play a pivotal role in a variety of vascular diseases. This project continues the initial theme of the project, related to effects of superoxide on endothelial function in atherosclerosis and after regression, with a new emphasis on thrombotic and antithrombotic mechanisms. The goal of Aim 1 is to study effects of an important antioxidant enzyme, extracellular superoxide dismutase (ECSOD) and a common human gene variant of that enzyme. The investigators reported that the heparin-binding domain (HBD) of ECSOD is essential for normal functon of ECSOD. A common gene variant in the HBD of ECSOD, R213G, may be an extremely important risk factor for ischemic heart disease. The investigators have made a recombinant adenovirus that expresses ECSOD R213G and propose to examine vascular effects of the gene variant. Studies are proposed to test the hypothesis that ECSOD, but not ECSOD R213G, attenuates inflammation and protects endothelial function after bacterial endotoxin. The goal of Aim 2 is to examine effects of atherosclerosis and ECSOD on endothelial antithrombotic func-tion and susceptibility to thrombosis in mice. Studies are proposed to test the hypothesis that accelerated thrombosis in atherosclerotic mice is caused by oxidative stress and decreased bioavailability of endothe-lium-derived nitric oxide, with decreased activation of anticoagulant protein C. Effects of atherosclerosis on endothelial antithrombotic function also will be examined in a novel strain of knock-in mice that express human thrombomodulin and have diminished capacity to activate anticoagulant protein C. The goal of Aim 3 is to examine effects of regression of atherosclerosis on endothelial vasomotor and anti-thrombotic function in mice. In """"""""Reversa"""""""" mice, hypercholesterolemia can be reversed with a genetic switch. After Cre induction, the gene for microsomal triglyceride transfer protein is virtually eliminated, so that plasma cholesterol in LDLr-/- apoB 100/100 mice is reduced to normal levels. Studies are proposed to test the hypothesis that regression of atherosclerosis in Reversa mice improves endothelial vasomotor function in aorta and coronary arteries, reduces superoxide in blood vessels and aortic valve, and reverses the enhanced susceptibility to thrombosis. The long-term goal of Project 3 is to clarify fundamental mechanisms by which superoxide and antioxidant enzymes modulate endothelial vasomotor and antithrombotic function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Iowa
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Doddapattar, Prakash; Jain, Manish; Dhanesha, Nirav et al. (2018) Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol 38:500-508
Hu, Xiaoming; De Silva, T Michael; Chen, Jun et al. (2017) Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 120:449-471
De Silva, T Michael; Hu, Chunyan; Kinzenbaw, Dale A et al. (2017) Genetic Interference With Endothelial PPAR-? (Peroxisome Proliferator-Activated Receptor-?) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. Hypertension 70:559-565
Dhanesha, Nirav; Doddapattar, Prakash; Chorawala, Mehul R et al. (2017) ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice. Arterioscler Thromb Vasc Biol 37:1332-1338
Chen, Zixin; Li, Yongjun; Yu, Hong et al. (2017) Isolation of Extracellular Vesicles from Stem Cells. Methods Mol Biol 1660:389-394
Shinohara, Keisuke; Liu, Xuebo; Morgan, Donald A et al. (2016) Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 68:1385-1392
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
Chu, Yi; Lund, Donald D; Doshi, Hardik et al. (2016) Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice. Arterioscler Thromb Vasc Biol 36:466-74
Hu, Chunyan; Lu, Ko-Ting; Mukohda, Masashi et al. (2016) Interference with PPAR? in endothelium accelerates angiotensin II-induced endothelial dysfunction. Physiol Genomics 48:124-34
Gu, Sean X; Blokhin, Ilya O; Wilson, Katina M et al. (2016) Protein methionine oxidation augments reperfusion injury in acute ischemic stroke. JCI Insight 1:

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