长期高同型半胱氨酸血症对高血压大鼠心脏重构的影响

Impact of long-term hyper-homocysteinemia on cardiac remolding in hypertensive rats

目的研究高同型半胱氨酸（Hcy）对自发性高血压（SHR）大鼠心脏重构的影响及叶酸、维生素B12的作用。方法7周龄SHR给予不同饮食喂养20周，分组如下：对照组给予不含蛋氨酸的普通全价配合饲料，蛋氨酸组给予添加2％蛋氨酸的饲料，治疗组同蛋氨酸组饲料喂养，自第9周添加B族维生素，维生素添加剂量为维生素B12 0．09mg·kg-1·d-1、叶酸4mg·kg-1·d-1，混合喂养组前8周同蛋氨酸组，后12周同对照组。测血浆Hcy、基质金属蛋白酶9（MMP-9）浓度，无创血压仪测量鼠尾血压，超声心动图及有创血流动力学检测心脏结构及功能，心室石蜡切片行天狼猩红染色。结果蛋氨酸组Hcy、MMP-9浓度明显升高，治疗组、混合喂养组与对照组Hcy浓度差异无统计学意义，蛋氨酸组心脏重量高于其他三组，收缩压低于对照组（P〈0．05）。与其他三组比较，蛋氨酸组左心室舒张末压（LVEDP）升高，左心室压力最大下降速度（-dp／dt max）降低，对照组、治疗组和混合喂养组差异无统计学意义；左心室短轴缩短率（LVFS）与左心室压力最大上升速度（＋dp／dt max）也以蛋氨酸组最低，治疗组接近对照组，混合喂养组低于对照组（P〈0．05）。蛋氨酸组大鼠血管周围纤维化高于其他三组，治疗组与对照组相同，混合喂养组高于对照组而与治疗组差异无统计学意义。各组心肌间质纤维沉积除治疗组纤维化程度低于混合喂养组外，其余组间变化趋势与血管周围纤维化相同。结论高Hcy可通过促进心肌间质纤维化和心肌间血管周围胶原沉积导致心脏重构，引起心脏舒张及收缩功能下降，叶酸、维生素B12可降低Hcy，部分逆转上述改变，保护心功能。

Objective To investigate the impact of hyper-homocystinemia （Hcy）on cardiac remolding in spontaneously hypertensive rat（SHR）and the protective effects of folic and vitamin B^2 on the remolding. Methods The seven-week-old SHR were divided into four groups according to different diet for 20 weeks. The control group was fed a perfect compound diet without methionine,the methionine group was fed a perfect compound diet added with 2 % methionine, the treatment group was fed as that of methionine group,but added with vitamin B12 0.09 mg/（kg, d）and folate 4 mg/（kg, d）in the last 12 weeks,the mixture group was fed as that of methionine group in the first 8 weeks,and as that of control group. At the end of the intervention period, plasma levels of Hcy and matrix metalloprotease（MMP）-9 were measured. The blood pressure was detected by the non-invasive blood pressure sensing device. The cardiac structure and function were detected using echocardiography and invasive hemodynamic method. Picro-sirius red（PSR）staining was used to check the fibrosis in paraffin embedding ventricle section. Results Plasma levels of Hey and MMP-9 were increased in the methionine group,while there was no significant difference in plasma levels of Hcy and MMP 9 among the treatment group, the mixture diet group and control group. Rats in methionine group had the largest heart weight among four groups, and systolic blood pressure was lower in methionine group than in the control group（P〈0.05）. Compared with the other three groups, the methionine group showed that the left ventricular end-diastolic pressure （LVEDP）was increased and -dp/dt max was decreased. Meanwhile, LVEDP and --dp/dt had no significant difference between the control group,treatment group and mixture group. The methionine group showed the most severe decrease in the left ventricular fractional shortening（ LVFS） and ＋dp/dt While LVFS and -dp/dt max had no statistical significance between the treatment group and control groups, but the mixture group had lower LVFS and ＋dp/dt values as compared with the control group（both P〈0.05）. Perivascular fibrosis was increased significantly in methionine group as compared with the other three groups,while the treatment and control groups had similar perivascular fibrosis, but the mixture group had higher perivascular fibrosis than did the control group, and had similar perivascular fibrosis to the treatment group. Fibrosis deposition in myocardium mesenchymal was similar to those observed in perivascular fibrosis, but the treatment group showed a more improvement of collagen deposition as compared with the mixture group. Conclusions Hyper-homocystinemia can accelerate systolic and diastolic dysfunction through accumulating fibrosis in myocardium and perivascular wall which lead to adverse cardiac remolding. Folate and vitamin B12 have protective effects on heart function by reversing the adverse changes through decreasing Hcy level.