Rosuvastatin Attenuates Pulmonary Arterial Hypertension in the Transgenic (mREN2)27 (Ren2) Rat

Abstract

Activation of the intrapulmonary renin‐angiotensin system in male transgenic Ren2 rats is associated with increases in lung oxidative stress, medial thickening of pulmonary arterioles, and pulmonary hypertension (PH). Statins are potent antioxidants and are vasculoprotective. We hypothesized that rosuvastatin (RSV) ameliorates PH and pulmonary vascular remodeling in Ren2 rats, in part, by reducing oxidative stress. Ren2 and Sprague‐Dawley (SD) rats were injected daily with RSV (10 mg/kg) for 3 wk, after which we measured right ventricular systolic pressure (RVSP) and mean arterial pressure (MAP). To evaluate remodeling, we measured the thickness of pulmonary arterioles. To evaluate oxidative stress in the lung we measured 3‐nitrotyrosine, NADPH oxidase activity, NOX2 and Rac1 expression, and ROS. Ren2 rats had elevations in MAP, RVSP, thickness of pulmonary arterioles, NADPH oxidase activity, Nox2 and Rac1, ROS, and 3‐nitrotyrosine compared to SD rats. RSV blunted the increase in RVSP, but not MAP, in the Ren2. RSV attenuated elevations in surface area of small pulmonary arteries, reduced NADPH oxidase activity and ROS, and 3‐nitrotyrosine, but did not blunt elevated levels of Nox2 and Rac1 protein expression in the Ren2. In summary, RSV reduces oxidative stress, pulmonary vascular remodeling and PH in male Ren2 rats. NIH R01‐HL‐63904 and VA Merit (JRS), and MU Research Board (VD).