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本研究旨在观察压力超负荷所致心肌肥厚的病理生理过程中是否发生细胞程序性坏死及洛沙坦对这一病理生理过程的影响。实验采用腹主动脉缩窄术(TAC)建立压力超负荷导致的心肌肥厚大鼠模型,通过动脉血压、超声心动图、左心室质量指数、心肌肥厚分子标志物等观察左心室的结构功能变化。用real-time PCR和Western blot法分别检测程序性坏死标志物——受体相互作用蛋白激酶1和3(RIPK1和RIPK3)的基因和蛋白表达变化。结果表明,SD大鼠TAC术后4周可发生心肌肥厚。心肌组织中RIPK1/RIPK3的表达升高,HE染色发现坏死样心肌组织,电镜结果显示线粒体结构受损,提示心肌细胞可能发生程序性坏死。给予TAC大鼠血管紧张素Ⅱ受体拮抗剂洛沙坦治疗,大鼠心脏结构及功能明显改善,心肌肥厚程度减轻,而且对心肌肥厚过程中的程序性坏死有明显的抑制作用。
This study aimed to observe the pathophysiology of cardiac hypertrophy caused by pressure overload whether programmed cell necrosis and losartan affect the pathophysiological process. The rat model of myocardial hypertrophy induced by pressure overload was established by abdominal aortic banding (TAC). The changes of left ventricular structural function were observed by arterial blood pressure, echocardiography, left ventricular mass index and molecular marker of cardiac hypertrophy. Real-time PCR and Western blot were used to detect the changes of the gene and protein expressions of the programmed necrosis marker-receptor interaction protein kinases 1 and 3 (RIPK1 and RIPK3) respectively. The results showed that cardiac hypertrophy occurred 4 weeks after TAC in SD rats. The expression of RIPK1 / RIPK3 in myocardium was increased. The necrotic myocardium was found by HE staining. The electron microscopy showed that the mitochondrial structure was impaired, which suggested that programmed cell necrosis might occur in cardiomyocytes. Administration of losartan, an angiotensin Ⅱ receptor antagonist, to TAC rats significantly improved cardiac structure and function, reduced cardiac hypertrophy, and markedly inhibited programmed necrosis during cardiac hypertrophy.