Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy
Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy
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DOI：
10.1172/jci13350
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发表时间：
2001-11-01
影响因子：
15.9
通讯作者：
Liao, JK
中科院分区：
文献类型：
--
作者：
Takemoto, M;Node, K;Liao, JK
心脏肥大是世界范围内发病率和死亡率的主要原因。肥大过程部分由Rho家族的小G蛋白介导。我们假设他汀类药物，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，通过阻断Rho异戊二烯化抑制心肌肥大。我们用血管紧张素II（AngII）加和不加辛伐他汀（Sim）处理新生大鼠心肌细胞，发现Sim降低AngII诱导的蛋白质含量、[H-3]亮氨酸摄取和心钠素（ANF）启动子活性。这些影响与细胞大小，膜Rho活性，超氧阴离子（O-2。(-))生产和细胞内氧化，并逆转与L-甲羟戊酸或香叶基香叶基焦磷酸，但不与法尼基焦磷酸或胆固醇。Rho抑制剂C3外毒素和细胞渗透性超氧化物歧化酶的治疗也降低了AngII诱导的O-2。(-)产生和肌细胞肥大。显性负性Rho突变体N17 Rac 1的过表达完全抑制AngII诱导的细胞内氧化和ANF启动子活性，而N19 RhoA部分抑制它，N17 Cdc 42没有效果。事实上，Sim抑制心肌肥大，降低心肌Rac 1活性和O-2。(-)在用AngII输注处理或经受经主动脉缩窄的大鼠中产生。这些发现表明，他汀类药物通过抑制Rac 1的抗氧化机制来预防心脏肥大的发展。
Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by small G proteins of the Rho family. We hypothesized that statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, inhibit cardiac hypertrophy by blocking Rho isoprenylation. We treated neonatal rat cardiac myocytes with angiotensin II (AngII) with and without simvastatin (Sim) and found that Sim decreased AngII-induced protein content, [H-3] leucine uptake, and atrial natriuretic factor (ANF) promoter activity. These effects were associated with decreases in cell size, membrane Rho activity, superoxide anion (O-2.(-)) production, and intracellular oxidation, and were reversed with L-mevalonate or geranylgeranylpyrophosphate, but not with farnesylpyrophosphate or cholesterol. Treatments with the Rho inhibitor C3 exotoxin and with cell-permeable superoxide dismutase also decreased AngII-induced O-2.(-) production and myocyte hypertrophy. Overexpression of the dominant-negative Rho mutant N17Rac1 completely inhibited AngII-induced intracellular oxidation and ANF promoter activity, while N19RhoA partially inhibited it, and N17Cdc42 had no effect. Indeed, Sim inhibited cardiac hypertrophy and decreased myocardial Rac1 activity and O-2.(-) production in rats treated with AngII infusion or subjected to transaortic constriction. These findings suggest that statins prevent the development of cardiac hypertrophy through an antioxidant mechanism involving inhibition of Rac1.