Endothelial dysfunction is associated with corresponding changes in vascular tone and increases in contractility, a condition that may cause hypertension in susceptible individuals which may have allelic variants in cyp2j-epoxygenases, soluble epoxide hydrolase (sEH), A2A, and A1 adenosine receptors (A2A AR &A1 AR) genes. These allelic variants may have similarities to our transgenic mice which may regulate vascular tone and blood pressure (BP). Our preliminary data have suggested a possible link between adenosine-induced relaxation and opening of KATP channels through A2A AR-cyp2j-PKA-PPAR? pathway. Also, it is possible that a link may exist between adenosine-induced contraction and closing of KATP channels through A1 AR-sEH-cyp4a- PPAR? pathway. A combination of pharmacological tools and transgenic mice would allow us to identify the possible targets as a long term goal to treat population which may have allelic variants leading to hypertension. Therefore, there is a critical need to explore the possible mechanism involving cyp2j2-epoxygenases, sEH/cyp4a, A1 AR/A2A AR, PPAR?/?, PKA/PKC?/? and KATP channels in adenosine-induced vascular responses. Our central hypothesis is that adenosine induces vascular relaxation and decreases in BP through cyp2j-epoxygenases via A2A AR-cyp2j-PKA-PPAR? signaling leading to opening of KATP channels. On the other hand, adenosine induces vascular contraction and increases in BP through sEH via A1 AR-sEH-cyp4a-PPAR? pathway leading to closing of KATP channels. To test this hypothesis, we propose to explore in depth mechanism(s) using A2A AR-/-, A1 AR-/-, cyp2j5-/-, sEH-/-, Tie2-cyp2j2Tr (endothelial-cyp2j2 overexpressed), Tie2-sEHTr (endothelial-sEH overexpressed), wild-type mice, immortal renal endothelial cell line from H-2Kb- tsA58 mouse, mouse aortic endothelial cells (MAEC) and mouse aortic smooth muscle cells (MASMC). Further, we will also explore the possible treatment with sEH inhibitors (AUDA/t-AUCB) in drinking water (or gavage) for A2A AR-/-, cyp2j5-/- and Tie2-sEHTr mice which may have high BP. We will measure BP, and we will use aortas/renal arteries (organ bath/DMT-wire myograph) with treatments (adenosine-receptors agonists &antagonists), cyp-epoxygenases, sEH, adenylyl cyclase, PKC?/?/, MAPK and PKA inhibitors, PPAR?/?, EETs and KATP channel (activators &inhibitors). EETs &DHETs will be analyzed (UPLC-MS/MS). Western blot &RT-PCR will be used for proteins &mRNA expression. We propose 3 specific aims to determine: (1) whether the cyp2j-epxygenases or sEH affects BP, adenosine-induced vascular response and EETs/DHETs;(2) whether the presence or absence of A2A AR affects adenosine-induced vascular response through PPARs via cyp2j-epoxygenases, sEH (3) whether the presence /overexpression of cyp2j-epoxygenases or sEH regulate KATP channels through A2A AR-cyp2j-PKA-PPAR?/A1 AR-sEH-cyp4a-PPAR? pathway in adenosine-induced vascular response. Such results can have a positive impact, as the identified components are expected to provide new targets to curb clinical problems linked with dysfunctional endothelium leading to hypertension.

Public Health Relevance

We propose to know the in-depth mechanism of blood pressure increase or decrease by using different drugs in special gene knockout and gene overexpressed mice. The outcome from this proposed study will provide us new targets or combination of targets for prevention as well as for the treatment of growing number of high blood pressure individuals in this country and the world.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114559-01A1
Application #
8501948
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Charette, Marc F
Project Start
2013-06-01
Project End
2017-03-31
Budget Start
2013-06-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$357,100
Indirect Cost
$115,816
Name
West Virginia University
Department
Physiology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2017) Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice. PLoS One 12:e0174137
Geldenhuys, W J; Khayat, M T; Yun, J et al. (2017) Drug Delivery and Nanoformulations for the Cardiovascular System. Res Rev Drug Deliv 1:32-40
Geldenhuys, Werner J; Hanif, Ahmad; Yun, June et al. (2017) Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases. Molecules 22:
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2017) Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ?-Hydroxylases. PLoS One 12:e0169584
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2017) Reduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor (t-AUCB): Role of adenosine A2A receptor and plasma oxylipins. Prostaglandins Other Lipid Mediat 131:83-95
Khayat, Maan T; Nayeem, Mohammed A (2017) The Role of Adenosine A2A Receptor, CYP450s, and PPARs in the Regulation of Vascular Tone. Biomed Res Int 2017:1720920
Yadav, Vishal R; Hong, Ka L; Zeldin, Darryl C et al. (2016) Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K(+) channels. Mol Cell Biochem 422:197-206
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2016) Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPAR?. PLoS One 11:e0162147
Pradhan, Isha; Ledent, Catherine; Mustafa, S Jamal et al. (2015) High salt diet modulates vascular response in A2AAR (+/+) and A 2AAR (-/-) mice: role of sEH, PPAR?, and K ATP channels. Mol Cell Biochem 404:87-96
Yadav, Vishal R; Nayeem, Mohammed A; Tilley, Stephen L et al. (2015) Angiotensin II stimulation alters vasomotor response to adenosine in mouse mesenteric artery: role for A1 and A2B adenosine receptors. Br J Pharmacol 172:4959-69

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