高同型半胱氨酸对高血压大鼠血管平滑肌细胞GRP78和CHOP的表达的影响与血管重构的关系

目的：观察同型半胱氨酸（Homocysteine，Hcy）对高血压大鼠内质网应激因子GRP78和CHOP表达及血管中层厚度变化，探讨Hcy对血管重构的影响。方法：采用腹主动脉缩窄术建立高血压大鼠模型，术后两周采用无创尾套法测量大鼠血压，选取24只成年雄性大鼠平均动脉压（MAP）〉150mmHg]随机等分为2组，即对照组和蛋氨酸组，每组12只（n=12）。对照组给予普通饮食＋双蒸水灌胃，蛋氨酸组给于30g/L蛋氨酸饮食＋双蒸水灌胃；根据实验结束的时间，又将各组分为4W和8W两个亚组，各亚组6只（n=6）。用同型半胱氨酸检测仪检测血清同型半胱氨酸浓度，用颈动脉插管法测定各组大鼠的MAP，并利用图像分析软件测量血管中层的厚度；HE染色观察大鼠主动脉血管形态学变化；通过免疫组化及Western blot检测大鼠主动脉血管平滑肌细胞（VSMCs）组织中GRP78及CHOP表达水平。结果：①对照组大鼠血清Hcy浓度在正常值范围（〈10μmol／L）；蛋氨酸组大鼠血清Hcy浓度明显高于对照组（P〈0．01）。②两组大鼠MAP均显著增高，4周时两者之间差异不明显，8周时两者差异显著（P〈0．05）；③蛋氨酸组大鼠血管平滑肌中层厚度显著大于对照组（P〈0．05）；④HE染色显示，与对照组相比，蛋氨酸组大鼠主动脉VSMCs显著肥大，管壁显著增厚；⑤两组CRP78和CHOP蛋白表达量增高，与对照组相比蛋氨酸组表达更明显。结论：高同型半胱氨酸可能通过促使高血压大鼠动脉VSMCs内质网应激反应，导致CRP78及CHOP的平衡失调加剧，从而引起血管损伤加重，而发生血管重构加重。

Influence of hyperhomocysteinemia on expressions of GRF78 and CHOP in hypertensive vascular smooth muscle cells and vascular remodeling

AIM： To observe the influence of hyperhomocysteinemia （Hhcy） on the expressions of GRP78 and CHOP in hypertensive rat vascular smooth muscle cells （VSMCs） and the vascular media thickness changes and to explore the impact of homocysteine （Hcy） on vascular remodeling. METHODS ： Fifty male Sprague Dawley rat models were induced by abdominal aorta constriction surgery. After 2 weeks, 24 rats with systolic blood pressure 〉 150 mmHg were randomly and equally divided into control group （ hypertensive rats fed with normal diet） and Hhcy group （hypertensive rats fed with homomethionine diet）. After 4 and 8 weeks, plasma homocysteine concentration was measured by homocysteine detector. Mean arterial pressure （MAP） was measured through carotid artery incubation and aorta media thickness was measured by image analysis software. Changes of vascular morphology in rat aorta were examined by HE staining and the expressions of GRP78 and CHOP in the vascular smooth muscle cells were examined by immunohistochemistry and Western blot. RESULTS： Compared with that in control group, plasma Hcy was significantly increased in Hhcy group （P 〈 0.01 ）. MAP was significantly increased in both control group and Hhcy group, with no statistical significance between groups after 4 weeks （P 〉 0. 05 ） but with statistical significance after 8 weeks （P 〈 0. 05）. Aortic media thickness in Hhcy group was significantly greater than in the control group （ P 〈 0.05 ）. Compared with those in the control group, the cell volume and arterial thickness were significantly increased in Hhcy group. GRP78 and CHOP protein expressions in both groups increased, with that in the Hhcy group being more obvious. CONCLUSIONS： High Hcy can aggravate vascular injury and result in vascular remodeling by increasing the endoplasmic reticulum stress response of hypertensive arterial smooth muscle cells and exacerbating the unbalance between GRP78 expression and activation of CHOP.