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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL019134-39
Application #
8650297
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
1977-09-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
39
Fiscal Year
2014
Total Cost
$552,012
Indirect Cost
$184,004
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Song, Chi Young; Khan, Nayaab S; Liao, Francesca-Fang et al. (2018) Brain Cytosolic Phospholipase A2? Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice. Am J Hypertens 31:622-629
Zou, Yanan; Chen, Zixuan; Jennings, Brett L et al. (2018) Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation. Sci Rep 8:1468
Pingili, Ajeeth K; Davidge, Karen N; Thirunavukkarasu, Shyamala et al. (2017) 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice. Hypertension 69:1104-1112
Khan, Nayaab S; Song, Chi Young; Thirunavukkarasu, Shyamala et al. (2016) Cytosolic Phospholipase A2? Is Essential for Renal Dysfunction and End-Organ Damage Associated With Angiotensin II-Induced Hypertension. Am J Hypertens 29:258-65
Pingili, Ajeeth K; Thirunavukkarasu, Shyamala; Kara, Mehmet et al. (2016) 6?-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice. Hypertension 67:916-26
Khan, Nayaab S; Song, Chi Young; Jennings, Brett L et al. (2015) Cytosolic phospholipase A2? is critical for angiotensin II-induced hypertension and associated cardiovascular pathophysiology. Hypertension 65:784-92
Pingili, Ajeeth K; Kara, Mehmet; Khan, Nayaab S et al. (2015) 6?-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice. Hypertension 65:1279-87
Jennings, Brett L; Moore, Joseph A; Pingili, Ajeeth K et al. (2015) Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice. Am J Physiol Renal Physiol 308:F981-92
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
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

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