Studies during the current period of funding have focused on cardiovascular effects of oxidative stress. The investigators observed oxidative stress in the aortic valve of "Reversa" (ldl"'7apoB^??'^??/Mttp'""/Mx1- Cre**) mice, and found that 1/3 ofthe mice develop moderately severe calcific aortic valvular stenosis (CAVS). The investigators now propose to test the hypotheses that 1) local and humoral mechanisms associated with oxidative stress and infiammation contribute to development of CAVS, and 2) mechanisms that reduce oxidative stress and infiammation inhibit development and progression of CAVS. A medical intervention to slow the progression of CAVS would be of great value. The invesfigators have demonstrated, with published and preliminary data, that two approaches can suppress signaling in the osteogenic pathway and reduce calcification of the aortic valve. Pharmacological interventions and complementary genetically altered mice will be used to examine mechanisms that may contribute to CAVS. The investigators will measure gene expression in aortic valves of mice, and function of the valve. One goal is to detennine whether osteoprotegerin (OPG), an endogenous decoy receptor of receptor- activator of NFKB ligand (RANKL), decreases expression of osteogenic genes, reduces calcification of the valve, and slows progression of aortic stenosis in mice with moderate aortic stenosis. Studies also are proposed to test the hypothesis that OPG deficiency (OPG"''mice) accelerates CAVS. The second goal is to determine whether two interacting endogenous systems, renin-angiotensin and PPARy, modulate development of CAVS. One hypothesis is that ATI receptors contribute to development of CAVS. Studies are planned to determine whether an antagonist of ATI receptors (but not an angiotensin- converting enzyme inhibitor) decreases expression of osteogenic genes and inhibits development of CAVS in Reversa mice. Studies also are planned to test the hypothesis that susceptibility to CAVS is reduced in ATlr"''mice. Finally, studies are planned to test the hypotheses that pioglitazone (a PPARy ligand) protects against development of CAVS in Reversa mice and, in endothelium-targeted dominant negative PPARy mice (E-V290M), susceptibility to CAVS is increased. The goal of this project is to use an experimental model of CAVS with hemodynamically significant stenosis to clarify molecular mechanisms of CAVS, functional consequences of calcification, and to explore possible therapeutic approaches.

Public Health Relevance

Calcific aortic valve stenosis (CAVS) is a common clinical problem, and is the second most common indication for cardiac surgery. These studies will determine whether three novel therapeutic interventions may slow, or reverse, the progression of CAVS. If any one of these approaches proves to be effective in slowing progression of CAVS, it could lead to clinical studies that fundamentally alter clinical treatment of CAVS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062984-13
Application #
8477961
Study Section
Special Emphasis Panel (ZHL1-PPG-P)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2013
Total Cost
$403,425
Indirect Cost
$136,256
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
De Silva, T Michael; Ketsawatsomkron, Pimonrat; Pelham, Christopher et al. (2015) Genetic interference with peroxisome proliferator-activated receptor ? in smooth muscle enhances myogenic tone in the cerebrovasculature via A Rho kinase-dependent mechanism. Hypertension 65:345-51
Zhang, Lan; Pan, Yaohua; Qin, Gangjian et al. (2014) Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: improving the safety of iPS cell transplantation to myocardium. Cell Cycle 13:762-71
Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8
Gould, Sarah T; Matherly, Emily E; Smith, Jennifer N et al. (2014) The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation. Biomaterials 35:3596-606
Dayal, Sanjana; Blokhin, Ilya O; Erger, Rochelle A et al. (2014) Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia. PLoS One 9:e107734
Peña Silva, Ricardo A; Kung, David K; Mitchell, Ian J et al. (2014) Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice. Hypertension 64:362-8
El Accaoui, Ramzi N; Gould, Sarah T; Hajj, Georges P et al. (2014) Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol 306:H1302-13
Joutel, Anne; Faraci, Frank M (2014) Cerebral small vessel disease: insights and opportunities from mouse models of collagen IV-related small vessel disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 45:1215-21
Grobe, Justin L; Sigmund, Curt D (2014) Another reason to eat your greens: cardiopulmonary protection by dietary delivery of angiotensin-converting enzyme-2 and angiotensin-(1-7) made in plants. Hypertension 64:1182-3
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

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