2,4,3′,5′‐Tetramethoxystilbene Reduces Blood Pressure and Associated Cardiac Fibrosis Via Inhibition of Cytochrome P450 1B1 and Decreased Oxidative Stress in SHR

Abstract

Previously, we reported that inhibition of cytochrome P450 (CYP) 1B1 activity with 2,4,3′,5′‐tetramethoxystilbene (TMS) reversed angiotensin II‐ and deoxycoticosterone acetate salt‐induced hypertension and associated pathophysiology in rats. This study was conducted to investigate the effect of TMS on blood pressure (BP), and associated cardiac fibrosis and oxidative stress in male, normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). TMS (600 μg/kg, i.p. daily for 6 weeks) beginning at 8 weeks of age, did not alter systolic BP in WKY, but decreased it in SHR (207 ± 7 mmHg vehicle, vs. 129 ± 2 mmHg TMS, P < 0.05). Cardiac CYP1B1 activity that was increased in SHR was reduced by TMS treatment. Cardiac fibrosis, as indicated by increased collagen deposition and myofibroblast accumulation, was observed in SHR, which was prevented by TMS. SHR had increased cardiac levels of reactive oxygen species, increased NADPH oxidase activity, and increased plasma levels of H2O2, NOx, and TBARS that were prevented by TMS, suggesting that in addition to inhibiting CYP1B1 activity and limiting cardiac damage, TMS regulates cardiac oxidative stress in SHR. These data suggest that CYP1B1 contributes to increased BP, cardiac damage, and associated oxidative stress in SHR. Moreover, CYP1B1 could serve as a novel target for the development of drugs such as TMS to treat cardiac disease associated with hypertension.