Our previous studies have shown that cytosolic phospholipase A2 (cPLA2) activated by calcium/calmodulin dependent kinase (CaMKII) in response to norepinephrine (NE) and angiotensin II (Ang II) releases AA and AA metabolites formed via lipoxygenase (LO) and cytochrome P450 (CYP), mainly hyroxyeicosatetraenoic acids (HETEs) result in activation of RasGTPase, extracellular signal regulated kinase ( ERK1/2) and contributes to the development of hypertension. Moreover, they cause activation of p38 mitogen activated protein kinase (MAPK) that in turn stimulates phospholipase D (PLD), epidermal growth factor receptor (EGFR) transactivation and increased Akt activity and vascular smooth muscle cells (VSMC) growth. The current proposal is extension of this work and is based on our novel preliminary findings that downregulation of CYP1B1 that is expressed in VSMC reduce Ang II-induced PLD activation, ERK1/2 and p38 MAPK phosphorylation, VSMC growth and development of hypertension. The central hypothesis of our proposal is that CPY1B1 which can metabolize AA into mid chain and terminal HETEs contributes to activation of various signaling molecules that are involved in VSMC growth, increased vascular reactivity and in the development of hypertension. To test our central hypothesis, we will address the following four specific aims. 1) To investigate the contribution of CYP1B1 in the metabolism of AA released from tissue phospholipids by Ang II and NE. 2) To determine the contribution of CYP1B1 to the action of Ang II and NE on various signaling molecules and VSMC growth. 3) To determine the contribution of CYP1B1 in Ang II- and DOCA-salt induced hypertension and in spontaneously hypertensive rats and in CYP1B1-/- and CY1B1P+/+ mice. 4) To investigate the contribution of CYP1B1 to the vascular reactivity in hypertensive and normotensive animals. The proposed studies will utilize cellular and molecular approaches including CYP1B1miRNA in lentivirus (LV) for gene silencing and CYP1B1cDNA for overexpression, and transgenic CYP1B1-/- and CYP1B1 +/+ mice. These studies should further our understanding of the mechanisms underlying vascular disease and allow identification of novel targets for the design of better therapeutic agents for the treatment of vascular diseases including hypertension.

Public Health Relevance

The proposed research should further our understanding of the mechanisms by which neuro-humoral factors regulate growth of vascular smooth muscle cells and contribute to the development and maintenance of high blood pressure. Moreover, it should allow us to identify new targets for the development of more effective agents for the treatment of vascular diseases including high blood pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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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
Tunctan, Bahar; Korkmaz, Belma; Sari, Ayse Nihal et al. (2013) 5,14-HEDGE, a 20-HETE mimetic, reverses hypotension and improves survival in a rodent model of septic shock: contribution of soluble epoxide hydrolase, CYP2C23, MEK1/ERK1/2/IKK?/I?B-?/NF-?B pathway, and proinflammatory cytokine formation. Prostaglandins Other Lipid Mediat 102-103:31-41
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
Buharalioglu, C Kemal; Korkmaz, Belma; Cuez, Tuba et al. (2011) Piroxicam reverses endotoxin-induced hypotension in rats: contribution of vasoactive eicosanoids and nitric oxide. Basic Clin Pharmacol Toxicol 109:186-94
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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