依那普利叶酸片对高血压伴高同型半胱氨酸血症大鼠左室肥厚干预的研究

Enalapril Maleate and Folic Acid Tables Intervention Effect of Left Ventricular Hypertrophy in SHR Rats with Hyperhomocysteinemia

目的:观察高同型半胱氨酸对高血压大鼠心肌内质网应激相关因子GRP94、caspase12表达的影响,及依那普利叶酸片(简称依叶片)对其表达的干预作用。方法:30只雄性成年自发性高血压大鼠(SHR),随机分为对照组、模型组和依叶片组,每组10只。对照组给予普通颗粒饲料喂养同时给予双蒸水灌胃,模型组给予含3%蛋氨酸的颗粒饲料喂养同时给予双蒸水灌胃,依叶片组给予含3%蛋氨酸的颗粒饲料喂养同时给予依叶片粉剂20 mg/kg/d灌胃。实验第8周末,用颈动脉插管法测各组大鼠平均动脉压(MAP),同型半胱氨酸检测仪检测血清同型半胱氨酸(homocystein,Hcy)浓度,称取体质量、全心质量及左心室质量计算大鼠心肌肥厚指数HWI及LVEI,通过HE染色观察心肌细胞形态学改变,免疫组化检测大鼠心肌组织中GRP94及caspase12表达水平。结果:①大鼠血清Hcy水平的变化。对照组大鼠血清Hcy值在正常值范围。与对照组相比,模型组大鼠血清Hcy值显著增高(P<0.01);与模型组相比,依叶片组大鼠血清Hcy值明显降低(P<0.01)。②大鼠HWI、LVEI及MAP的变化。模型组大鼠的HWI及LVEI均明显高于对照组(P<0.05);依叶片干预后大鼠的HWI及LVEI均明显降低(P<0.05)。对照组与模型组大鼠的MAP均明显增高,但两组大鼠的MAP差异无统计学意义(P>0.05);与模型组相比,依叶片干预后大鼠的MAP明显降低(P<0.01)。③大鼠心肌细胞内质网应激(endoplasmic reticulum stress,ERS)相关因子GRP94及caspase12表达。对照组及模型组大鼠心肌细胞GRP94及caspase12表达均增高。与对照组相比,模型组大鼠心肌细胞GRP94、caspase12表达增高更为明显(P<0.05)。依叶片干预后大鼠心肌细胞GRP94、caspase12表达明显降低(P<0.05)。结论:高Hcy通过ERS途径使高血压大鼠左室肥厚程度加重;依叶片可有效降低血清Hcy及血压水平,抑制心肌细胞ERS,从而有效逆转左室肥厚,其对左室肥厚干预的分子机制为"H型"高血压的预防及治疗提供了新的理论依据。

Objective： To observe the influence of hyperhomocysteine on the expression of the correlation factors GRP94 and caspase12 of endoplasmic reticulum stress in SHR rat heart, and the intervention effect of Enalapril Maleate and Folic Acid Tables against it. Methods： Thirty male SHR rats were randomly divided into control group（hypertensive rats by feeding normal die group）, model group（hypertensive rats by feeding 3% methionin die group） and EMFA group（hypertensive rats by feeding 3% methionin die plus Enalapril Maleate and Folic Acid Tables [20 mg/kg/d）] treatment）. After 8 weeks treatment, plasma homocystein, HWI, LVWI and mean arterial pressure（MAP） were measured, expression of GRP94 and caspase12 in rat myocardial tissues were examined by immunohistochmistry. Results： ①In control group, serum Hcy concentration was in the normal range, and it was dramatically higher in model group than that in control group（P〈0.01）, and that was lower in EMFA group than in model group（P〈0.01）. ②The index of left ventricular hypertrophy HWI, LVWI were significantly higher in model group than that in control group（P〈0.05）, and that was lower in EMFA group than in model group（P〈0.05）. ③The average value of MAP was significantly increased in control group and model group, but there was no significant statistical difference between the two groups（P〉0.05）. Compared with model group, the average value of MAP significantly decreased in EMFA group（P〈0.01）. ④ The average values of protein expressions of GRP94 and caspase12 were higher in model group than those in control group（P〈0.05）, and those were lower in EMFA group than those in control group（P〈0.05）. Conclusions： Hyperhomocysteine may be involved in ERS, which may exacerbate ERS induced by hypertension, and eventually results in an increase in left ventricular hypertrophy. Enalapril Maleate and Folic Acid Tables can effectively reduce plasma homocystein and blood pressure levels, inhibit ERS, thus improve left ventricular hypertrophy. The molecular mechanisms provides a new theoritical basis for prevention and treatment of H-type hypertension.