Peptide interaction in regulating vascular NOS

Abstract

The aim of this study was to examine the role of the serine/threonine kinase, Akt, signaling pathway in mediating interactions between angiotensin II (Ang II) and insulin-like growth factor-1 (IGF-1) in the regulation of nitric-oxide synthase (NOS) activity in vascular smooth muscle cells (VSMC). To investigate the role of Ang II, aortic and heart tissue obtained from transgenic rats overexpressing the mouse Ren-2 gene (hypertensive mREN rats) and Sprague-Dowley (SD) rats were treated with the AT1 receptor agonist, Valsratan (30 mg/kg/day). In VSMC obtained from the 2 models, exposure to IGF-1 (100 nM) for 10 min resulted in increased NOS activity and NO production. IGF-1 treatment induces Akt phosphorylation at Ser473 and Thr308, as well as Akt kinase activity. Pretreatment with Ang II (100 nM) for 5 min substantially decreased these IGF-1 effects; NOS activity was decreased in mREN rats compared to SD animals. Following the treatment of mREN animals with Valsartan for 2 weeks, the NOS activity was found to be similar to the levels in SD controls. Akt phosphorylation at Ser473 was attenuated in aortic tissue in untreated mREN when compared to SD, while no differences were found in the phosphorylation at Thr308 between the two strains. In heart tissue the level of Akt phosphorylation at Ser473 was increased in Valsartan treated animals compared to untreated mREN. These results demonstrate a role for Akt in the Ang II/IGF-1 regulation of NOS in VSMC and cardiac tissue, and show that the AT1 blocker was successful in correcting some of the abnormalities.