Horiuchi Masatsugu, Cui Tai-Xing, Li Zhen, Li Jian-Mei, Nakagami Hironori, Iwai Masaru
Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan.
Circulation. 2003 Jan 7;107(1):106-12. doi: 10.1161/01.cir.0000043244.13596.20.
The present studies were undertaken to investigate the potential effect of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular neointimal formation and to explore the cellular mechanism of cross-talk of the AT1 receptor and statin in vascular smooth muscle cells (VSMCs).
Neointimal formation and the proliferation of VSMCs induced by cuff placement around the femoral artery were significantly inhibited by treatment with an ARB, valsartan, at a dose of 0.1 mg x kg(-1) x d(-1) and with fluvastatin at a dose of 1 mg x kg(-1) x d(-1), which did not influence mean arterial blood pressure or plasma cholesterol level, whereas valsartan or fluvastatin alone at these doses did not affect neointimal formation or the proliferation of VSMCs. Pretreatment with fluvastatin (approximately 5 micromol/L) for 24 hours significantly inhibited Ang II (1 micromol/L)-mediated DNA synthesis and c-fos promoter activity in cultured VSMCs. Moreover, pretreatment of VSMCs with fluvastatin significantly inhibited Ang II-mediated extracellular signal-regulated kinase (ERK) activation and tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. AT1 receptor-mediated recruitment of Rac-1 to Janus kinase (Jak) family/STATs was also inhibited by fluvastatin. Consistent with these in vitro results, phosphorylation of ERK, STAT1, and STAT3 was attenuated by the coadministration of valsartan and fluvastatin even at low doses in vivo.
These results suggest that the cholesterol-independent inhibition of AT1 receptor-mediated VSMC proliferation by statins may contribute to the beneficial effects of statins combined with an ARB on vascular diseases.
本研究旨在探讨羟甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）增强血管紧张素（Ang）II 1型（AT1）受体阻滞剂（ARB）对血管内膜增生抑制作用的潜在效应，并探索AT1受体与他汀类药物在血管平滑肌细胞（VSMC）中相互作用的细胞机制。
通过在股动脉周围放置套管诱导的内膜增生和VSMC增殖，分别用剂量为0.1 mg·kg⁻¹·d⁻¹的ARB缬沙坦和剂量为1 mg·kg⁻¹·d⁻¹的氟伐他汀治疗后受到显著抑制，且这两种药物不影响平均动脉血压或血浆胆固醇水平，而单独使用这些剂量的缬沙坦或氟伐他汀对内膜增生或VSMC增殖没有影响。用氟伐他汀（约5 μmol/L）预处理24小时可显著抑制培养的VSMC中Ang II（1 μmol/L）介导的DNA合成和c-fos启动子活性。此外，用氟伐他汀预处理VSMC可显著抑制Ang II介导的细胞外信号调节激酶（ERK）激活以及信号转导和转录激活因子（STAT）1和STAT3的酪氨酸和丝氨酸磷酸化。氟伐他汀还抑制了AT1受体介导的Rac-1向Janus激酶（Jak）家族/STATs的募集。与这些体外结果一致，即使在体内低剂量联合使用缬沙坦和氟伐他汀时，ERK、STAT1和STAT3的磷酸化也会减弱。
这些结果表明，他汀类药物对AT1受体介导的VSMC增殖的胆固醇非依赖性抑制作用可能有助于他汀类药物与ARB联合使用对血管疾病的有益作用。
