Role of AT-1 receptor in regulation of vascular MCP-1, IL-6, PAI-1, MAP kinase, and matrix expressions in obesity.

Role of AT-1 receptor in regulation of vascular MCP-1, IL-6, PAI-1, MAP kinase, and matrix expressions in obesity. Background. Metabolic syndrome has emerged as the major cause of atherosclerosis. The associated atherosclerosis is accompanied by and, in part, due to inflammation. In an attempt to explore the molecular sources of vascular inflammation and possible involvement of renin-angiotensin system, we studied obese Zucker rats, which exhibit all features of metabolic syndrome. Methods. Seven-week-old male obese Zucker rats were randomized to losartan-treated (100 mg/L drinking H(2)O) and untreated groups. Lean Zucker rats served as controls. After four months, aortas were obtained and processed for various determinations by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot and immunohistochemical analysis for collagen type IV. Results. Compared to the lean controls, obese Zucker rats showed significant increases in collagen staining, as well as expressions of collagen, fibronectin, plasminogen activator inhibitor-1, and two major proinflammatory mediators (i.e., interleukin-6 and monocyte chemoattractant protein-1). This was associated with significant increases in p38 and ERK1/2 mitogen activated protein kinase activities, as well as marked up-regulation of angiotensin II type 1 receptor (AT-1R) mRNA expression. These abnormalities were prevented by administration of the AT-1R blocker (ARB). Conclusion. The untreated obese Zucker rats exhibit increased matrix protein accumulation in the aorta and marked up-regulations of proinflammatory and profibrotic pathways. These abnormalities are associated with up-regulation of AT-1R and are prevented by AT-1R blockade pointing to the potential role of AT-1R activation.