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 #
5P01HL034300-27
Application #
8256755
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
2012-04-01
Budget End
2013-03-31
Support Year
27
Fiscal Year
2012
Total Cost
$2,285,707
Indirect Cost
$650,066
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Wu, Cheng-Chia; Gupta, Tanush; Garcia, Victor et al. (2014) 20-HETE and blood pressure regulation: clinical implications. Cardiol Rev 22:1-12
Abraham, Nader G; Sodhi, Komal; Silvis, Anne M et al. (2014) CYP2J2 targeting to endothelial cells attenuates adiposity and vascular dysfunction in mice fed a high-fat diet by reprogramming adipocyte phenotype. Hypertension 64:1352-61
Capdevila, Jorge H; Pidkovka, Nataliya; Mei, Shaojun et al. (2014) The Cyp2c44 epoxygenase regulates epithelial sodium channel activity and the blood pressure responses to increased dietary salt. J Biol Chem 289:4377-86
Hinds Jr, Terry D; Sodhi, Komal; Meadows, Charles et al. (2014) Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity (Silver Spring) 22:705-12
Cheng, Jennifer; Edin, Matthew L; Hoopes, Samantha L et al. (2014) Vascular characterization of mice with endothelial expression of cytochrome P450 4F2. FASEB J 28:2915-31
Hao, Shoujin; Bellner, Lars; Zhao, Hong et al. (2014) NFAT5 is protective against ischemic acute kidney injury. Hypertension 63:e46-52
Chen, Li; Ackerman, Rachel; Saleh, Mohamed et al. (2014) 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. J Pharmacol Exp Ther 348:442-51
Issan, Yossi; Kornowski, Ran; Aravot, Dan et al. (2014) Heme oxygenase-1 induction improves cardiac function following myocardial ischemia by reducing oxidative stress. PLoS One 9:e92246
Wang, Wen-Hui; Zhang, Chengbiao; Lin, Dao-Hong et al. (2014) Cyp2c44 epoxygenase in the collecting duct is essential for the high K+ intake-induced antihypertensive effect. Am J Physiol Renal Physiol 307:F453-60
Sodhi, K; Puri, N; Kim, D H et al. (2014) PPARýý binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats. Int J Obes (Lond) 38:456-65

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