洛伐他汀对醛固酮诱导鼠心肌成纤维细胞增殖及其 iNOS-NO 系统活性的调控作用

摘要

目的：探讨洛伐他汀对醛固酮诱导心肌成纤维细胞（ CFs）增殖及诱导型一氧化氮合酶-一氧化氮（ iN-OS-NO）系统活性的调控作用。方法用胰酶消化法分离、培养新生SD大鼠CFs，采用MTT比色法、硝酸还原酶法、分光光度法和半定量RT-PCR技术，观察不同浓度洛伐他汀对CFs增殖、NO含量、iNOS活性和iNOS mRNA表达的影响。结果洛伐他汀（1×10-8～1×10-5 mol/L）能剂量依赖性抑制醛固酮诱导CFs的增殖，升高CFs的NO含量、iNOS活性及增加iNOS mRNA的表达（P均＜0．05），甲羟戊酸（1×10-3 mol/L）、法尼酯焦磷酸（5μmol/L）可完全逆转洛伐他汀的上调作用。洛伐他汀干预下醛固酮诱导CFs的NO生成量与iNOS活性、iNOS活性与iNOS mRNA表达均呈正相关（r分别为0．826、0．752，P均＜0．01）；CFs增殖数目与NO含量呈负相关（r＝-0．908，P＜0．01）。结论洛伐他汀可上调醛固酮诱导CFs的iNOS-NO系统活性，抑制CFs增殖，并呈剂量依赖性，其作用机制可能与甲羟戊酸途径调节有关。%Objective To investigate the effects of Lovastatin on the aldosterone-induced proliferation of rat cardiac fi-broblasts(CFs) and the activity of inducible nitric oxide synthase (iNOS).Methods CFs were isolated from neonatal Sprague Dawley rats by trypsin digestion.MTT colorimetric assay was used to evaluate cell proliferation.Nitric acid reduc-tase method, spectrophotometry and reverse transcription-polymerase chain reaction were used to detect the NO contents, iNOS activity and iNOS mRNA expression respectively.Results Lovastatin(1 ×10 -8 -1 ×10 -5 mol/L) inhibited the proliferation of CFs increased NO contents and iNOS activity in a dose-depend manner(P<0.05), which could be reversed by mevalonate(1 ×10 -3 mol/L) or farnesyl pyrophosphate(5μmol/L).NO contents and iNOS activity, iNOS activity and iNOS mRNA expression were positively correlate induced by different concentrations of Lovastatin(r=0.826, 0.752, re-spectively, all P<0.01).The proliferation of CFs was significant negatively correlated with NO contents induced by differ-ent concentrations of Lovastatin(r=-0.908, P<0.01).Conclusions The results indicate that Lovastatin up-regulated iNOS-NO system in CFs, and inhibite proliferation of CFs in a dose-depenent manner, which can be related to the regula-tion of mevalonate pathway.