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.
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.
|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-ÎºB 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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