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.
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