Yao Hai-Mu, Wu Xue-Si, Zhang Jing, Geng Bin, Tang Chao-Shu
Department of Cardiology, Beijing Anzhen Hospital, Capital University of Medical Science, Beijing 100029, China.
Sheng Li Xue Bao. 2006 Apr 25;58(2):116-23.
To investigate the anti-cardiac hypertrophic mechanism of statins, thirty-eight male Wistar rats were randomly allocated to four groups. Rats in model group received nitric oxide synthase inhibitor, N-nitro-L-arginine (L-NNA) 15 mg/(kg.d) by peritoneal injection. Rats in simvastatin treatment groups were given simultaneously L-NNA as those in model group and simvastatin 5 or 30 mg/(kg.d) intragastrically respectively. Rats in control group received the same volume of normal sodium. Left ventricular function, left ventricular mass index (LVMI), the content of brain natriuretic peptide (BNP) in plasma and myocardium, myocardial hydroxyproline and heme oxygenase activity were determined after 6 weeks. The results showed that rats in model group developed significant cardiac hypertrophy associated with reduced left ventricular function compared with the control group. However, compared with the model group, L-NNA-induced cardiac hypertrophy of rats was significantly relieved in simvastatin treatment groups, associated with improved left ventricular function, decreased LVMI, lower BNP levels in plasma and myocardium, lower content of myocardial hydroxyproline, and increased myocardial heme oxygenase (HO) activity. In cultured rat neonatal cardiomyocytes, simvastatin (30 or 100 mumol/L) significantly increased heme oxygenase-1 (HO-1) mRNA expression, HO activity as well as the production of CO in cardiomyocytes. Cultured with zinc protoporphyrin, a HO inhibitor, or simvastatin alone did not change [(3)H]leucine uptake of cardiomyocytes. However, cocultured with simvastatin significantly inhibited the cardiomyocyte [(3)H]leucine uptake induced by angiotensin II in a concentration-dependent manner. Cotreatment with zinc protoporphyrin significantly abolished the suppressive effect of simvastatin on cardiomyocyte [(3)H]leucine uptake. These data suggest that the activation of HO-1/CO pathway may be one of the important mechanisms by which statins inhibit cardiac hypertrophy caused by hypertension.
为研究他汀类药物抗心脏肥大的机制，将38只雄性Wistar大鼠随机分为四组。模型组大鼠腹腔注射一氧化氮合酶抑制剂N-硝基-L-精氨酸（L-NNA），剂量为15mg/（kg·d）。辛伐他汀治疗组大鼠在腹腔注射L-NNA的同时，分别给予辛伐他汀5mg/（kg·d）或30mg/（kg·d）灌胃，剂量同模型组。对照组大鼠给予等体积的生理盐水。6周后测定左心室功能、左心室质量指数（LVMI）、血浆及心肌中脑钠肽（BNP）含量、心肌羟脯氨酸含量及血红素加氧酶活性。结果显示，与对照组相比，模型组大鼠出现明显的心脏肥大，左心室功能降低。然而，与模型组相比，辛伐他汀治疗组大鼠L-NNA诱导的心脏肥大明显减轻，左心室功能改善，LVMI降低，血浆及心肌中BNP水平降低，心肌羟脯氨酸含量降低，心肌血红素加氧酶（HO）活性增加。在培养的大鼠新生心肌细胞中，辛伐他汀（30或100μmol/L）显著增加心肌细胞中血红素加氧酶-1（HO-1）mRNA表达、HO活性以及CO生成。用HO抑制剂锌原卟啉单独培养或单独用辛伐他汀培养均不改变心肌细胞的[³H]亮氨酸摄取。然而，与辛伐他汀共培养可浓度依赖性地显著抑制血管紧张素II诱导的心肌细胞[³H]亮氨酸摄取。与锌原卟啉共同处理可显著消除辛伐他汀对心肌细胞[³H]亮氨酸摄取的抑制作用。这些数据表明，HO-1/CO途径的激活可能是他汀类药物抑制高血压所致心脏肥大的重要机制之一。
