This proposal is an extension of the previous work and is aimed to test the hypothesis that Group IV cytosolic phospholipase A2 (cPLA2?)plays a critical role in the pathogenesis of hypertension and hypertension- associated target-organ damage. This novel hypothesis is based on intriguing preliminary data that cPLA2? gene disruption in mice (cPLA2?-/-) ameliorates both Ang II- and DOCA-salt-induced hypertension. Moreover, cPLA2? gene disruption prevents Ang II-induced target-organ damage (as evidence by reductions in cardiovascular dysfunction, cardiac and renal fibrosis in cPLA2?-/- mice). cPLA2? gene disruption also ameliorates Ang II-induced renal infiltration of macrophages and T lymphocytes, suggesting alterations in hypertension-induced immune system activation. More imporantly, cPLA2? gene disruption prevents production of reactive oxygen species (ROS) in subfornical organ (SFO) in the central nervous system associated with Ang II-induced hypertension, effects that are reversed by expression of adenovirus (Ad) cPLA2? DNA in the SFO of cPLA2?-/- mice. To investigate the innovative concept that cPLA2? is involved in the pathogenesis of hypertension and end organ damage, the following specific aims will be addressed.
Aim 1. To determine the contribution of cPLA2? to Ang II- and DOCA-salt-induced hypertension.
Aim 2. To determine the contribution of cPLA2? to Ang II- and DOCA-salt-induced target-organ damage.
Aim 3. To determine the contribution of cPLA2? to Ang II- and DOCA-salt-induced immune system activation.
Aim 4. To determine the role of cPLA2? to Ang II and DOCA-salt-induced changes in the central nervous system. To accomplish the objective of these aims, the state-of-the-art in vivo and in vitro cellular and molecular biology and histologicl and immunohistochemical techniques will be used. These include: a) 1) cPLA2?+/+ and cPLA2?- /- mice;2) Adenovirus (Ad) cPLA2? shRNA and Ad cPLA2? DNA;3) telemetry for measuring BP and echocardiography for assessing cardiac function;4) histological, immunohistochemical, and fluorescence microscopy and biochemical techniques;5) flow cytometry to determine immune cell population in the blood and tissues;6) T cells from the spleen of transgenic mice to determine the mechanism of cPLA2?-induced NADPH oxidase activity and ROS production;and 7) HPLC-LC-ESI-MS to measure eicosanoids and other possible AA metabolites. The proposed studies will provide novel insights into the mechanism linking cPLA2? to activation of NADPH oxidase and the immune system in the development of hypertension and its pathogenesis. Moreover, these studies should allow to demonstrate that cPLA2? is a potential target for developing novel, selective, water-soluble inhibitors of this enzyme for treating hypertension and associated target-organ damage and for stimulating further basic and clinical research to determine possible polymorphisms in the cPLA2? gene in hypertension and cardiovascular and renal diseases.

Public Health Relevance

The proposed studies will provide an insight into the mechanism linking cytosolic phospholipase A2? (cPLA2?), an enzyme that promotes release of the fatty acid arachidonic acid, to activation of NADPH oxidase, an enzyme that generates reactive oxygen species, and the immune system in the development and pathogenesis of high blood pressure. Moreover, our studies will demonstrate cPLA2? as a potential target for the development of novel agents for treating high blood pressure and associated cardiovascular-renal dysfunction and end organ damage.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hypertension and Microcirculation Study Section (HM)
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Maric-Bilkan, Christine
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University of Tennessee Health Science Center
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Jennings, Brett L; Montanez, David E; May Jr, Michael E et al. (2014) Cytochrome P450 1B1 contributes to increased blood pressure and cardiovascular and renal dysfunction in spontaneously hypertensive rats. Cardiovasc Drugs Ther 28:145-61
Jennings, Brett L; George, L Watson; Pingili, Ajeeth K et al. (2014) Estrogen metabolism by cytochrome P450 1B1 modulates the hypertensive effect of angiotensin II in female mice. Hypertension 64:134-40
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Tunctan, Bahar; Korkmaz, Belma; Sari, Ayse Nihal et al. (2013) Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91(phox) to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock. Nitric Oxide 33:18-41
Jennings, Brett L; Anderson, Larry J; Estes, Anne M et al. (2012) Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin II in mice. Hypertension 59:348-54
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Jennings, Brett L; Sahan-Firat, Seyhan; Estes, Anne M et al. (2010) Cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiology. Hypertension 56:667-74
Yaghini, Fariborz A; Song, Chi Young; Lavrentyev, Eduard N et al. (2010) Angiotensin II-Induced Vascular Smooth Muscle Cell Migration and Growth Are Mediated by Cytochrome P450 1B1-Dependent Superoxide Generation. Hypertension :
Sahan-Firat, Seyhan; Jennings, Brett L; Yaghini, Fariborz A et al. (2010) 2,3',4,5'-Tetramethoxystilbene prevents deoxycorticosterone-salt-induced hypertension: contribution of cytochrome P-450 1B1. Am J Physiol Heart Circ Physiol 299:H1891-901
Tunctan, Bahar; Yaghini, Fariborz A; Estes, Anne et al. (2008) Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production. Arch Pharm Res 31:856-65

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