| Adenosine plays a central role in various vascular functions, although the importance of its different receptors in mediating these effects has not been fully elucidated. This thesis focuses on the role of the A2b adenosine receptor (A2bAR) in vascular and metabolic functions. The A2bAR controls inflammation via its expression in bone marrow cells, and we found that A2bAR knockout (KO) on C57BL background results in upregulation of vascular adhesion molecules. When subjected to high fat diet, these mice developed a Type II diabetic profile characterized by high blood glucose, impaired glucose clearance, increased levels of plasma insulin, fat to muscle ratio, leptin and lipids.;To assess this receptor's role in atherosclerosis, we generated A2bAR KO mice on an apolipoprotein E (ApoE) null background and subjected them to high-fat diet. Atherosclerosis measured by oil-red-o, histology, and ultrasound, was more pronounced in the absence of the A2bAR. This was associated with elevated levels of plasma cholesterol and triglycerides concentrated in very low density lipoprotein particles. A similar increase in lipids was observed in the liver, a phenotype typical of steatosis. A2bAR bone marrow (BM) signals post BM-transplantation had no effect on atherosclerosis. Gene expression analysis of A2bAR KO livers, confirmed by western blotting, pointed to elevated levels of the transcription factor sterol response element binding protein-1 (SREBP-1). Protein levels of the SREBP-1 targets, acetyl-CoA carboxylase and fatty acid synthase were also elevated in the livers of A2bAR KO. Pharmacological inhibition or activation of A2bAR in primary hepatocytes isolated from ApoE KO mice led to elevation or downregulation of SREBP-1, respectively. In vivo, adenoviral restoration of this receptor in the liver resulted in reduction of plasma triglycerides and cholesterol. This reduction was associated with decreased levels of acetyl-CoA carboxylase and fatty acid synthase.;This study is the first to highlight the significance of the A2bAR in regulating SREBP-1 levels and consequent development of hyperlipidemia and atherosclerosis, as well as to suggest a role for this receptor in Type II diabetes. |
