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目的:探讨洛伐他汀抑制醛固酮诱导心肌成纤维细胞(CFs)增殖的信号转导机制。方法:用胰酶消化法分离、培养新生大鼠CFs,采用3 H-胸腺嘧啶核苷(3 H-TdR)掺入法、Western-blotting技术从DNA合成、蛋白表达等方面观察丝裂原活化蛋白激酶(MAPK)活化与洛伐他汀抑制醛固酮诱导CFs增殖的关系。结果:洛伐他汀以浓度依赖方式抑制醛固酮诱导CFs DNA合成。10-3 mol/L甲羟戊酸(MVA)和5μmol/L法尼酯焦磷酯(FPP)能完全逆转10-5 mol/L洛伐他汀对醛固酮诱导的CFs 3 H-TdR掺入率的抑制作用。10-5 mol/L洛伐他汀可降低10-7 mol/L醛固酮诱导的CFs的MAPK蛋白磷酸化。10-3 mo1/L MVA和5μmol/L FPP具有逆转洛伐他汀下调CFs磷酸化MAPK蛋白水平的作用。结论:洛伐他汀可通过MVA途径抑制醛固酮促CFs增殖作用,且洛伐他汀通过阻断醛固酮诱导的MAPK活化而发挥作用。
Objective: To investigate the mechanism of lovastatin inhibiting aldosterone-induced proliferation of cardiac fibroblasts (CFs). Methods: Newborn rat CFs were isolated and cultured by trypsin digestion, and mitochondria activation was observed by 3 H-TdR incorporation and Western-blotting from DNA synthesis and protein expression Relationship between activation of protein kinase (MAPK) and inhibition of aldosterone - induced proliferation of CFs by lovastatin. RESULTS: Lovastatin inhibited aldosterone-induced CFs DNA synthesis in a concentration-dependent manner. 10-3 mol / L mevalonic acid (MVA) and 5μmol / L farnesol phophate (FPP) completely reversed the aldosterone-induced incorporation rate of 3 H-TdR into CFs Inhibition. Lovastatin at 10-5 mol / L reduced MAPK protein phosphorylation of 10-7 mol / L aldosterone-induced CFs. 10-3 mol / L MVA and 5 mol / L FPP reversed the effect of lovastatin on down-regulation of phosphorylated MAPK protein levels in CFs. Conclusion: Lovastatin can inhibit aldosterone-induced proliferation of CFs through MVA pathway, and lovastatin can block aldosterone-induced MAPK activation.