Peroxisome Proliferator–Activated Receptor γ Regulates Angiotensin II–Stimulated Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase in Blood Vessels In Vivo

Abstract

Angiotensin (Ang) II is implicated in hypertension, vascular remodeling, and insulin resistance. Peroxisome proliferator–activated receptor (PPAR) γ activators increase insulin sensitivity and improve Ang II–induced vascular remodeling. We evaluated the effects of the PPAR-γ activator rosiglitazone on Ang II signaling in aorta and mesenteric arteries. Rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Blood pressure rise in Ang II–infused rats was attenuated by rosiglitazone. Ang II significantly increased Ang II type 1 receptor expression in the mesenteric arteries ( P <0.001), whereas that of the aorta was decreased ( P <0.05), changes which were reversed by rosiglitazone. Akt activity was increased by Ang II and returned to basal levels under rosiglitazone in both vascular beds. However, Ang II–induced extracellular signal–regulated kinase 1/2 activity increased in aorta but not in mesenteric vessels ( P <0.001), where 4E-binding protein 1 activity was significantly increased by Ang II and inhibited by PPAR-γ activation. In response to Ang II, Src homology (SH) 2–containing inositol phosphatase 2 activity was increased ( P <0.05) in both vascular beds. In conclusion, PPAR-γ activator rosiglitazone attenuated Ang II–induced blood pressure elevation and intracellular signaling on aorta and mesenteric vessels. There was differential inhibition of Ang II type 1 receptor receptors/phosphatidylinositol 3-kinase/Akt and extracellular signal–regulated kinase 1/2 in both vessels. Effects of PPAR-γ activators on these pathways could contribute to regression of vascular remodeling in models of hypertension and diabetes and, accordingly, in hypertensive diabetic patients.