Increased vascular dysfunction is a manifestation of obesity and its associated risk factors and is a prelude to the development of vascular disease and its clinical manifestations such as hypertension and diabetes. Diet-induced obesity is an increasing health problem and little is known ofthe underlying mechanisms linking obesity to vascular dysfunction and hypertension. We have shown that in obesity there are decreased levels of HO-1, EET and adiponectin, key anti-oxidative and anti-inflammatory pathways for vascular protection and homeostasis. The central hypothesis argues that adipocyte-derived EETs are integral components of the HO-1-adiponectin axis and are critical for the control of adipocyte function and resistance to vascular dysfunction in obesity. We hypothesize that these three protective pathways are inextricably linked forming a functional module and a deficiency in any of these components leads to adipocyte and vascular dysfunction that is associated with obesity and hypertension. Accordingly, Aim 1 will characterize HO protein and activity in murine MSC-derived adipocytes and examine whether an increase in HO-1 increases adipocyte function, adiponectin and EET production and whether EET inhibition abrogates the HO-1-mediated increase in adipocyte function.
Aim 2 will characterize adipocyte epoxygenase activity in murine MSC-derived adipocytes, the role of endogenous EET, EET's effect on adipocyte function and whether targeted deletion of HO-1 abrogates the sparing effect of EETs on adipocyte function.
Aim 3 will determine whether adipocyte specific overexpression of HO-1 is sufficient to prevent adiposity, vascular dysfunction and hypertension in mice fed a high fat diet and whether EETs are essential component of the HO-1 protective functions.
Aim 4 will determine whether adipocytes cell-specific expression of epoxygenase-EET is sufficient to prevent adiposity, vascular dysfunction and hypertension in mice fed a high fat diet and whether HO-1 is necessary for EET protective functions. These studies will provide novel molecular mechanisms governing EET-HO interplay in the regulation of adipocyte-vascular interactions and a framework for translating adipocyte protection to the clinical arena of obesity, vascular dysfunction and hypertension.

Public Health Relevance

Understanding the cellular and molecular mechanisms governing adipocyte-vascular interactions will lead to the development of therapeutic strategies to fight vascular dysfunction and hypertension seen in obesity with the expectation that this will result in improving the quality of life and life expectancy of the obese, insulin resistant patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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New York Medical College
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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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