Abstract 427: Mammalian Target of Rapamycin (mTOR) Inhibition Attenuates Angiotensin II-Induced Hypertension and Endothelial Dysfunction

Abstract

Angiotensin (Ang) II produces hypertension, endothelial dysfunction as well as vascular hypertrophy. mTOR is a key regulator of cell growth and protein synthesis, however the contribution of mTOR to hypertension and endothelial dysfunction produced by Ang II has not been previously elucidated. The goal of this study was to test the hypothesis that mTOR contributes to the hypertension and endothelial dysfunction produced by Ang II. C57Bl/6 mice were infused (via osmotic minipump) with vehicle or rapamycin (an inhibitor of mTOR; 2 mg/kg/d) for 10 days following which mice were then infused with Ang II (1000 ng/kg/min) plus vehicle or rapamycin for 14 subsequent days. Systolic blood pressure (SBP) was measured on Days -10, 0, and 14 using tail-cuff plethysmography and vascular function was examined in carotid arteries (in vitro) on Day 14. Ang II infusion produced a significant degree (P<0.05) of hypertension in wild-type mice (eg, SBP: 114±4 vs. 145±3 mmHg on Day 0 and Day 14 of Ang II infusion, respectively). In rapamycin-treated mice, Ang II infusion had no effect (P>0.05) on SBP (eg, SBP: 110±6 vs. 116±9 mmHg, on Day 0 and Day 14 of co-infusion of rapamycin plus Ang II, respectively). Rapamycin alone or vehicle infusion had no effect (P>0.05) on blood pressure during Day -10 through Day 0. In terms of endothelial responses, acetylcholine-induced relaxation was impaired (P<0.05) in Ang II-infused mice by approximately 50%. In contrast, rapamycin was associated with a significant degree of protection against Ang II-induced endothelial dysfunction (eg, 100 μM acetylcholine produced 47±10 vs. 90±4% relaxation in carotid arteries from Ang II- and Ang II plus rapamycin-infused mice, respectively). Tempol, a scavenger of superoxide was very effective in improving endothelial responses in Ang II-infused mice. Molecular analysis revealed that Ang II-infusion was associated with increased mTOR expression as well as mTOR phosphorylation. Taken together, these data provide strong pharmacologic and molecular evidence that mTOR activity contributes to the hypertension and endothelial dysfunction produced by Ang II.