Essig M, Nguyen G, Prié D, Escoubet B, Sraer J D, Friedlander G
INSERM U 426 and the Department of Physiology, Faculté de Médecine Xavier Bichat, Université Denis Diderot, Paris, France.
Circ Res. 1998 Oct 5;83(7):683-90. doi: 10.1161/01.res.83.7.683.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HRIs) have been recently shown to prevent atherosclerosis progression. Clinical benefit results from combined actions on various components of the atherosclerotic lesion. This study was designed to identify the effects of HRI on one of these components, the endothelial fibrinolytic system. Aortas isolated from rats treated for 2 days with lovastatin (4 mg/kg body wt per day) showed a 3-fold increase in tissue plasminogen activator (tPA) activity. In a rat aortic endothelial cell line (SVARECs) and in human nontransformed endothelial cells (HUVECs), HRI induced an increase in tPA activity and antigen in a time- and concentration-dependent manner. In SVARECs, the maximal response was observed when cells were incubated for 48 hours with 50 micromol/L HRI. An increase of tPA mRNA was also in evidence. In contrast, HRI inhibited plasminogen activator inhibitor-1 activity and mRNA. The effects of HRI were reversed by mevalonate and geranylgeranyl pyrophosphate, but not by LDL cholesterol and farnesyl pyrophosphate, and were not induced by alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of protein farnesyl transferase. C3 exoenzyme, an inhibitor of the geranylgeranylated-activated Rho protein, reproduced the effect of lovastatin on tPA and plasminogen activator inhibitor-1 activity and blocked its reversal by geranylgeranyl pyrophosphate. The effect of HRI was associated with a disruption of cellular actin filaments without modification of microtubules. A disrupter of actin filaments, cytochalasin D, induced the same effect as lovastatin on tPA, whereas a disrupter of microtubules, nocodazole, did not. In conclusion, HRI can modify the fibrinolytic potential of endothelial cells, likely via inhibition of geranylgeranylated Rho protein and disruption of the actin filaments. The resulting increase of fibrinolytic activity of endothelial cells may contribute to the beneficial effects of HRI in the progression of atherosclerosis.
3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂（HRIs）最近已被证明可阻止动脉粥样硬化进展。临床益处源于对动脉粥样硬化病变各种成分的联合作用。本研究旨在确定HRIs对这些成分之一，即内皮纤维蛋白溶解系统的影响。从用洛伐他汀（每天4mg/kg体重）处理2天的大鼠分离的主动脉显示组织纤溶酶原激活物（tPA）活性增加了3倍。在大鼠主动脉内皮细胞系（SVARECs）和人未转化的内皮细胞（HUVECs）中，HRIs以时间和浓度依赖性方式诱导tPA活性和抗原增加。在SVARECs中，当细胞与50μmol/L HRIs孵育48小时时观察到最大反应。tPA mRNA也有增加。相反，HRIs抑制纤溶酶原激活物抑制剂-1活性和mRNA。HRIs的作用被甲羟戊酸和香叶基香叶基焦磷酸逆转，但不被低密度脂蛋白胆固醇和法尼基焦磷酸逆转，并且不被蛋白质法尼基转移酶抑制剂α-羟基法尼基膦酸诱导。C3外切酶，一种香叶基香叶基化激活的Rho蛋白抑制剂，重现了洛伐他汀对tPA和纤溶酶原激活物抑制剂-1活性的作用，并阻断了香叶基香叶基焦磷酸对其的逆转。HRIs的作用与细胞肌动蛋白丝的破坏有关，而微管未发生改变。肌动蛋白丝破坏剂细胞松弛素D对tPA产生与洛伐他汀相同的作用，而微管破坏剂诺考达唑则没有。总之，HRIs可能通过抑制香叶基香叶基化的Rho蛋白和破坏肌动蛋白丝来改变内皮细胞的纤维蛋白溶解潜能。内皮细胞纤维蛋白溶解活性的增加可能有助于HRIs在动脉粥样硬化进展中的有益作用。
