The objective of this Program Project Grant continues to concentrate on the role of the cytochrome P450 (CYP)-derived eicosanoids in the regulation of renal and vascular function and in the control of blood pressure. This Program provided paradigms and scientific leads for a framework of CYP-eicosanoid research in the field of hypertension. The relevance ofthis research to human health is highlighted in recent studies by Program investigators and others demonstrating the molecular and functional association between CYP-eicosanolds and cardiovascular disease including diabetes, stroke and hypertension. This proposal builds on this foundation and brings novel concepts and new directions to this area of research. It incorporates the vascular and renal mechanisms and the inflammatory component of hypertension in terms of interactions between the CYP-derived eicosanoids, EETs and 20-HETE, and two distinct regulatory circuits, the renin-angiotensin system (RAS) and the heme oxygenases (HO). This theme is depicted in three projects. Project 1 focuses on the interactions between the CYP4A-derived 20-HETE and the renin angiotensin system and investigate the role of endothelial ACE in 20-HETE-mediated vascular dysfunction and hypertension. Project 2 examines the role of K+ intake and angiotensin II in regulating the inhibitory effect of CYP2C44-dependent EETs on sodium transport (epithelial Na+ channel) in the cortical collecting duct and its impact on hypertension. Project 3 determines the molecular mechanisms by which an interplay between HO-1 and EETs modulates adipocyte function and adiponectin levels to prevent the development of vascular dysfunction in obesity-induced hypertension. These projects will be supported by three Cores: Core A provides administrative support. Core B provides LC-MS/MS-based measurements of eicosanoids. Core C provides molecular, genotypic and phenotypic support for animal research. This Program Project combines interdisciplinary approach to explore the integrative biology of EETs and HETEs, key modulators of renal salt handling, vascular endothelial integrity and vascular tone, in the pathophysiology of hypertension and cardiovascular disease. The objective of this Program Project Grant continues to concentrate on the role of the cytochrome P450 (CYP)-derived eicosanoids in the regulation of renal and vascular function and in the control of blood pressure. This Program provided paradigms and scientific leads for a framework of CYP-eicosanoid research in the field of hypertension. The relevance ofthis research to human health is highlighted in recent studies by Program investigators and others demonstrating the molecular and functional association between CYP-eicosanolds and cardiovascular disease including diabetes, stroke and hypertension. This proposal builds on this foundation and brings novel concepts and new directions to this area of research. It incorporates the vascular and renal mechanisms and the inflammatory component of hypertension in terms of interactions between the CYP-derived eicosanoids, EETs and 20-HETE, and two distinct regulatory circuits, the renin-angiotensin system (RAS) and the heme oxygenases (HO). This theme is depicted in three projects. Project 1 focuses on the interactions between the CYP4A-derived 20-HETE and the renin angiotensin system and investigate the role of endothelial ACE in 20-HETE-mediated vascular dysfunction and hypertension. Project 2 examines the role of K+ intake and angiotensin II in regulating the inhibitory effect of CYP2C44-dependent EETs on sodium transport (epithelial Na+ channel) in the cortical collecting duct and its impact on hypertension. Project 3 determines the molecular mechanisms by which an interplay between HO-1 and EETs modulates adipocyte function and adiponectin levels to prevent the development of vascular dysfunction in obesity-induced hypertension. These projects will be supported by three Cores: Core A provides administrative support. Core B provides LC-MS/MS-based measurements of eicosanoids. Core C provides molecular, genotypic and phenotypic support for animal research. This Program Project combines interdisciplinary approach to explore the integrative biology of EETs and HETEs, key modulators of renal salt handling, vascular endothelial integrity and vascular tone, in the pathophysiology of hypertension and cardiovascular disease. ular tone, in the pathophysiology of hypertension and cardiovascular disease.

Public Health Relevance

Hypertension, obesity and diabetes are leading causes of cardiovascular and renal disease morbidity and mortality, and their prevalence, complexity, and multiple clinical and socio-economical consequences make them a major health challenge. The molecular basis of these diseases needs to be fully defined. This Program Project provides a unique Interdisciplinary approach to broaden our understanding and identify new targets for therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL034300-29
Application #
8644831
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
1997-09-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
29
Fiscal Year
2014
Total Cost
$2,251,547
Indirect Cost
$638,499
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Abraham, Nader G; Junge, Joshua M; Drummond, George S (2016) Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome. Trends Pharmacol Sci 37:17-36
Singh, Shailendra P; Schragenheim, Joseph; Cao, Jian et al. (2016) PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid. Prostaglandins Other Lipid Mediat 125:8-18
Kizub, Igor V; Lakhkar, Anand; Dhagia, Vidhi et al. (2016) Involvement of gap junctions between smooth muscle cells in sustained hypoxic pulmonary vasoconstriction development: a potential role for 15-HETE and 20-HETE. Am J Physiol Lung Cell Mol Physiol 310:L772-83
Peterson, Stephen J; Vanella, Luca; Gotlinger, Katherine et al. (2016) Oxidized HDL is a potent inducer of adipogenesis and causes activation of the Ang-II and 20-HETE systems in human obese females. Prostaglandins Other Lipid Mediat 123:68-77
Garcia, Victor; Shkolnik, Brian; Milhau, Laura et al. (2016) 20-HETE Activates the Transcription of Angiotensin-Converting Enzyme via Nuclear Factor-κB Translocation and Promoter Binding. J Pharmacol Exp Ther 356:525-33
Froogh, Ghezal; Qin, Jun; Kandhi, Sharath et al. (2016) Female-favorable attenuation of coronary myogenic constriction via reciprocal activations of epoxyeicosatrienoic acids and nitric oxide. Am J Physiol Heart Circ Physiol 310:H1448-54
Qin, Jun; Le, Yicong; Froogh, Ghezal et al. (2016) Sexually dimorphic adaptation of cardiac function: roles of epoxyeicosatrienoic acid and peroxisome proliferator-activated receptors. Physiol Rep 4:
Wang, Wen-Hui (2016) Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity. Curr Opin Nephrol Hypertens 25:429-35
Paudyal, Mahesh P; Adebesin, Adeniyi Michael; Burt, Scott R et al. (2016) Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 353:1144-7
Liu, Jiang; Tian, Jiang; Chaudhry, Muhammad et al. (2016) Attenuation of Na/K-ATPase Mediated Oxidant Amplification with pNaKtide Ameliorates Experimental Uremic Cardiomyopathy. Sci Rep 6:34592

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