Carbon monoxide attenuates Ang II‐induced vascular hypertrophy via inhibition of NOX1

Angiotensin II (Ang II) is a critical mediator of hypertension and vascular hypertrophy. Also, Ang II is a potent inducer of NADPH oxidase (NOX)‐derived reactive oxygen species, which stimulate signaling cascades leading to VSMC hypertrophy. Induction of heme oxygenase‐1 was shown to lower blood pressure in animal models of hypertension. Here we studied the effect of carbon monoxide (CO) on Ang II‐induced NOX activity and vascular smooth muscle cell (VSMC) hypertrophy in vitro and hypertension and vascular hypertrophy in vivo. VSMC were treated with Ang II (100 nM) with or without CO donor (100 μM) or CO gas (250 ppm) pretreatment. Ang II increased NOX activity and VSMC hypertrophy, which was blunted by CO. NOX1 (but not NOX4) siRNA blunted Ang II‐induced NOX activity and hypertrophy suggesting that CO inhibited Nox1 in these cells. In mice, hypertension was induced by delivery of AngII (750 mg/kg/day) by osmotic minipump. Control mice were treated with saline. A subset of the mice was exposed to CO (250 ppm 1h/day). Ang II increased systolic blood pressure, which was not affected by CO. In carotid arteries, CO inhibited Ang II‐induced medial hypertrophy indicating that CO could prevent hypertrophy independent of effects on blood pressure. These results reveal a novel role of CO in maintaining vascular homeostasis as well as the potential use of pharmacological CO and/or manipulation of HO‐1 in the treatment of hypertension.