Control of vascular disease and glucose and insulin homeostasis by the A2b adenosine receptor
Johnston-Cox, Hillary A.
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Cardiovascular disease remains a leading cause of mortality. Risk factors, including poor glycemic control, central obesity and dyslipidemia contribute to prothrombotic and proinflammatory states, which elevate the risk for adverse cardiovascular events. Identifying new pharmacological targets for glycemic control is essential for prevention and management of cardiovascular disease. Adenosine is an endogenous purine nucleoside released from various tissues following stress, or produced externally by ecto-nucleotidases. Adenosine modulates inflammation and influences the metabolic state. There are four adenosine receptors classified as adenylyl cyclase activating (A2a and A2b) or inhibiting (A1 and A3). Using an A2b adenosine receptor (A2bAR) knockout (KO) mouse, our laboratory previously showed that A2bAR protects against atherosclerosis. Subjecting A2bAR, Apolipoprotein E (ApoE) double KO mice to a high fat diet (HFD) led to augmented liver levels of the transcription factor sterol response element binding protein-1 (SREBP-1) and its downstream targets, cholesterol and triglycerides, as well as to increased atherosclerosis, compared to mice with normal A2bAR. The studies in this thesis showed that selective restoration of hepatic A2bAR by adenovirus mediated gene transfer, or in vivo administration of an A2bAR agonist, BAY 60-6853, reduced the lipid profile and atherosclerosis. This study identified the A2bAR as a therapeutic target for hyperlipidemia and atherosclerosis. Liver steatosis is often associated with impaired hepatic insulin signaling. To test the hypothesis that A2bAR controls glucose/insulin homeostasis, A2bAR KO mice, with normal ApoE background, were subjected to HFD. Compared to control mice, A2bAR KO mice developed obesity and hallmarks of type 2 diabetes (T2D). We identified a novel link between expression of A2bAR and insulin receptor substrate 2 (IRS-2). IRS-2 is downregulated and insulin signaling is impaired in tissues of A2bAR KO mice that exhibit a greater inflammatory state. Importantly, pharmacological activation of A2bAR under HFD, using BAY 60-6583, restored IRS-2 levels, and ameliorated T2D. In obese human subjects, A2bAR expression correlated strongly with IRS-2 expression. Taken together, our study identifies the A2bAR as a significant regulator of HFD-induced hallmarks of atherosclerosis and T2D, with dysregulated liver A2bAR expression being a common denominator. Our study points to A2bAR as a therapeutic target for these disorders.
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