Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21WAF1
Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21WAF1
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DOI：
10.1007/s00210-012-0768-5
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发表时间：
2012-10-01
影响因子：
3.6
通讯作者：
Li, Shaojun
中科院分区：
文献类型：
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作者：
Li, Manxiang;Liu, Yuan;Li, Shaojun
辛伐他汀是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，通过抑制肺动脉平滑肌细胞（PASMCs）的增殖来改善肺动脉高压的发生，但其分子机制尚不完全清楚。在这项研究中，我们发现，辛伐他汀剂量依赖性地抑制阿糖胞苷刺激的PASMCs增殖。这伴随着血红素加氧酶-1（HO-1）的平行诱导和p21（WAF 1）的上调。更重要的是，我们发现锡原卟啉（SnPP），HO-1的选择性抑制剂，可以阻断辛伐他汀对5-羟色胺抑制细胞增殖的作用，并取消辛伐他汀诱导的p21（WAF 1）表达。辛伐他汀对细胞增殖的抑制作用也被siRNA转染沉默p21（WAF 1）显著抑制。SnPP对细胞增殖的抑制作用程度与siRNA转染p21（WAF 1）缺失的抑制作用相似。综上所述，我们的研究表明，辛伐他汀抑制PASMCs增殖，通过顺序上调HO-1和p21（WAF 1），以改善肺动脉高压。
Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, which has been shown to ameliorate the development of pulmonary hypertension in animal model by suppression of pulmonary artery smooth muscle cells (PASMCs) proliferation, yet its underlying molecular mechanisms are not completely understood. In this study, we show that simvastatin dose-dependently inhibited serotonin-stimulated PASMCs proliferation. This was accompanied with the parallel induction of heme oxyganase-1 (HO-1) and upregulation of p21(WAF1). More importantly, we found that Tin-protoporphyrin (SnPP), a selective inhibitor of HO-1, could block the effect of simvastatin on inhibition of cell proliferation in response to serotonin and abolish simvastatin-induced p21(WAF1) expression. The inhibitive effect of simvastatin on cell proliferation was also significantly suppressed by silencing p21(WAF1) with siRNA transfection. The extent of effect of SnPP on inhibition of cell proliferation was similar to that of lack of p21(WAF1) by siRNA transfection. Taken together, our study suggests that simvastatin inhibits PASMCs proliferation by sequential upregulation of HO-1 and p21(WAF1) to benefit pulmonary hypertension.