Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

Background-3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibi tors (statins) have effects that extend beyond cholesterol reduction. We us ed an angiotensin (Ang) II-dependent model to test the hypothesis that ceri vastatin ameliorates cardiac injury. Methods and Results-We treated rats transgenic for human renin and angioten sinogen (dTGR) chronically from weeks 4 to 7 with cerivastatin (0.5 mg/kg, by gavage). We used immunohistochemistry, electrophoretic mobility shift as says, and reverse transcription-polymerase chain reaction techniques. Compa red with control dTGR, dTGR treated with cerivastatin had reduced mortality , blood pressure, cardiac hypertrophy, macrophage infiltration, and collage n I, laminin, and fibronectin deposition. Basic fibroblast growth factor mR NA and protein expression were markedly reduced, as was interleukin-6 expre ssion. The transcription factors NF-kappaB and AP-1 were substantially less activated, although plasma cholesterol was not decreased. Conclusions-These results suggest that statins ameliorate Ang II-induced hy pertension, cardiac hypertrophy, fibrosis, and remodeling independently of cholesterol reduction. Although the clinical significance remains uncertain , the results suggest that statins interfere with Ang II-induced signaling and transcription factor activation, thereby ameliorating end-organ damage.