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.
|Wang, Lijun; Zhang, Chengbiao; Su, Xiao-Tong et al. (2017) PGF2? regulates the basolateral K channels in the distal convoluted tubule. Am J Physiol Renal Physiol 313:F254-F261|
|Garcia, Victor; Gilani, Ankit; Shkolnik, Brian et al. (2017) 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res 120:1776-1788|
|Bowden, John A; Heckert, Alan; Ulmer, Candice Z et al. (2017) Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J Lipid Res 58:2275-2288|
|Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286|
|Pandey, Varunkumar; Garcia, Victor; Gilani, Ankit et al. (2017) The Blood Pressure-Lowering Effect of 20-HETE Blockade in Cyp4a14(-/-) Mice Is Associated with Natriuresis. J Pharmacol Exp Ther 363:412-418|
|Sodhi, Komal; Srikanthan, Krithika; Goguet-Rubio, Perrine et al. (2017) pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet. Sci Rep 7:193|
|Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65|
|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:|
|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|
|Su, Xiao-Tong; Zhang, Chengbiao; Wang, Lijun et al. (2016) Disruption of KCNJ10 (Kir4.1) stimulates the expression of ENaC in the collecting duct. Am J Physiol Renal Physiol 310:F985-93|
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