Wang Hui-Ping, Zhang Wen-Hui, Wang Xiao-Fang, Zhu Jin, Zheng Yan-Qian, Xia Qin, Zhi Jian-Ming
Experimental Research Center, Shanghai Jiaotong University Affiliated First People's Hospital, 650 New Songjiang Road, Shanghai 201620, China.
Department of Physiology, School of Medicine, Shanghai Jiaotong University, 280 Chongqing South Road, Shanghai 200025, China.
Int J Mol Sci. 2014 Jun 27;15(7):11495-509. doi: 10.3390/ijms150711495.
Epidemiological studies have demonstrated that women with a history of preeclampsia have a two-fold increased risk of developing cardiovascular diseases in later life. It is not known whether or not this risk is associated with angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of AT1 receptor (AT1R), which is believed to be involved in the pathogenesis of preeclampsia. The objective of the present study was to confirm the hypothesis that AT1-AA exposure during pregnancy may change the maternal cardiac structure and increase the susceptibility of the postpartum heart to ischemia/reperfusion injury (IRI). In the present study, we first established a preeclampsia rat model by intravenous injection of AT1-AA extracted from the plasma of rats immunized with AT1R, observed the susceptibility of the postpartum maternal heart to IRI at 16 weeks postpartum using the Langendorff preparation, and examined the cardiac structure using light and transmission electron microscopy. The modeled animals presented with symptoms very similar to the clinical symptoms of human preeclampsia during pregnancy, including hypertension and proteinuria. The left ventricular weight (LVW) and left ventricular mass index (LVMI) in AT1-AA treatment group were significantly increased as compared with those of the control group (p < 0.01), although there was no significant difference in final weight between the two groups. AT1-AA acting on AT1R not only induced myocardial cell hypertrophy, mitochondrial swelling, cristae disorganization and collagen accumulation in the interstitium but affected the left ventricular (LV) function and delayed recovery from IRI. In contrast, co-treatment with AT1-AA + losartan completely blocked AT1-AA-induced changes in cardiac structure and function. These data indicate that the presence of AT1-AA during pregnancy was strongly associated with the markers of LV geometry changes and remodeling, and increased the cardiac susceptibility to IRI in later life of postpartum maternal rats.
流行病学研究表明，有子痫前期病史的女性在晚年患心血管疾病的风险增加两倍。尚不清楚这种风险是否与1型血管紧张素II受体自身抗体（AT1-AA）有关，AT1-AA是一种通过激活AT1受体（AT1R）起作用的激动剂，据信其参与了子痫前期的发病机制。本研究的目的是证实以下假设：孕期暴露于AT1-AA可能会改变母体心脏结构，并增加产后心脏对缺血/再灌注损伤（IRI）的易感性。在本研究中，我们首先通过静脉注射从用AT1R免疫的大鼠血浆中提取的AT1-AA建立了子痫前期大鼠模型，在产后16周使用Langendorff装置观察产后母体心脏对IRI的易感性，并使用光学显微镜和透射电子显微镜检查心脏结构。建模动物在孕期出现的症状与人类子痫前期的临床症状非常相似，包括高血压和蛋白尿。与对照组相比，AT1-AA治疗组的左心室重量（LVW）和左心室质量指数（LVMI）显著增加（p<0.01），尽管两组的最终体重没有显著差异。作用于AT1R的AT1-AA不仅诱导心肌细胞肥大、线粒体肿胀、嵴紊乱和间质胶原积累，还影响左心室（LV）功能并延迟IRI后的恢复。相反，AT1-AA与氯沙坦联合治疗完全阻断了AT1-AA诱导的心脏结构和功能变化。这些数据表明，孕期存在AT1-AA与LV几何形状改变和重塑的标志物密切相关，并增加了产后母鼠晚年心脏对IRI的易感性。
