There is a delicate balance between pathways which promote oxidative stress and inflammation, through stressors such as angiotensin II and hypercholesterolemia, and pathways which are protective by promoting an antioxidant and antiinflammatory state. The balance/imbalance between these pathways influences susceptibility to atherosclerosis, hypertension, calcific aortic valvular stenosis, and thrombosis. The overall theme of this Program is to define endogenous mechanisms that protect against, and predispose to, cardio- vascular dysfunction and disease. The Projects in this Program will focus on several novel hypotheses. First, findings during the current funding period indicate that PPAR? dependent pathways in both endothelium and vascular smooth muscle protect against development of atherosclerosis. Studies are proposed to examine mechanisms of protection by PPAR? and to test the hypothesis that PPAR? protects against thrombosis and calcific aortic valvular stenosis. These studies are timely and clinically relevant considering the controversy about effects of thiazoledinedione drugs, which activate PPAR?. Second, the renin-angiotensin system is a key mechanism in pathophysiology of hypertension and stroke. Studies are proposed to test the hypothesis that the renin- angiotensin system contributes to cerebral vascular dysfunction, calcific aortic valvular stenosis, and thrombosis. Third, mechanisms will be studied by which PPAR? modulates rho kinase turnover and activity, and thus may contribute to altered vascular structure and vasomotor tone in hypertension. Fourth, studies are planned to test the hypothesis that a specific oxidation reaction, protein methionine oxidation, impairs anti-coagulant function of the endothelial protein thrombomodulin, and thereby contributes to the prothrombotic phenotype of atherosclerosis. The Program is tightly focused and cohesive. It consists of four projects and three cores. The investigators use sophisticated experimental approaches, including tissue-specific genetically altered mice, to clarify fundamental mechanisms. The investigators are productive, highly interactive, and the environment is outstanding. If major goals of the Program are accomplished, which is probable based on the track record and synergy of the investigators, the findings will clarify important mechanism related to cardiovascular dysfunction, and may allow translation into improved treatment of atherosclerosis and other cardiovascular diseases.
The goal of these studies is to define fundamental mechanisms that protect against, or ultimately lead to, several cardiovascular diseases. The studies focus on molecular pathways which have direct implications for understanding mechanisms of action of drugs that are used widely in patients. The studies have direct relevance to patient care by clarifying mechanisms of drugs that are commonly used, and may potentially lead to novel approaches that will alter clinical treatment.
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|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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