Effects of rosuvastatin correlated with the down-regulation of CYP4A1 in spontaneously hypertensive rats.

The effects of long-term rosuvastatin treatment on the regulation of cytochrome P450 (CYP) 4A1 expression and vascular homeostasis of spontaneously hypertensive rat (SHR) are still unknown. In this study SHRs were randomly divided into three groups (n=10 per group): SHR group, H-Rv group (rosuvastatin 2.5 mg·kg(-1)·d(-1)), L-Rv group (rosuvastatin 0.5 mg·kg(-1)·d(-1)), and 10 male Wistar-Kyoto (WKY) rats in the control group (WKY group). All rats were treated with rosuvastatin for 12 weeks. The systolic blood pressure (SBP), left ventricle weight index (LVWI) and plasma lipids were measured during or after treatment. The expression of CYP4A1 mRNA and protein in different tissues was detected by real-time PCR and Western blot. In the heart, kidney and aorta, the CYP4A1 expressions were down-regulated at both mRNA and protein levels in rosuvastatin-treated groups compared with the untreated SHR group (P<0.05 or P<0.01), and high-dose rosuvastatin exerted a stronger down-regulatory effect. The increasing trend of blood pressure was markedly blunted in the rosuvastatin-treated groups versus the untreated SHR group, and a stronger effect was observed in high-dose group (P<0.05 and P<0.01 at different time points). LVWI, an indicator of ventricle hypertrophy, was improved in the high-dose group compared with the untreated SHR group (P<0.05). The plasma concentrations of TC, TG and LDL-C in three SHR groups (high-dose, low-dose and untreated group) were all significantly lower than those of WKY group (P<0.05 or P<0.01), which seemed unrelated to the treatment of rosuvastatin. These findings suggested that hypertension in SHRs was possibly associated with CYP4A1 overexpression, and the effects of rosuvastatin on blood pressure and ventricle hypertrophy were potentially correlated with CYP4A1 and its metabolite other than lipid profiles. Multiple mechanisms are likely involved in the beneficial effects of statins with respect to the regulation of CYP4A1.

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