Angiotensin II Type 2 Receptor Stimulation A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?
Angiotensin II Type 2 Receptor Stimulation A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?
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DOI：
10.1161/circulationaha.108.784868
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发表时间：
2008-12-09
期刊：
影响因子：
37.8
通讯作者：
Steckelings, U. Muscha
中科院分区：
文献类型：
--
作者：
Kaschina, Elena;Grzesiak, Aleksandra;Steckelings, U. Muscha
背景-本研究首次使用新型非肽类血管紧张素Ⅱ 2型（AT 2）受体激动剂化合物21（C21）检测直接刺激AT 2受体对梗死后心脏功能的影响。方法和结果-通过永久性结扎左冠状动脉在Wistar大鼠中诱导心肌梗死（MI）。MI后24小时开始C21（0.01、0.03、0.3 mg/kg/天IP）给药，并持续至人道处死（MI后7天）。通过磁共振成像评估动脉瘤大小，并通过经胸多普勒超声心动图和心内Millar导管进行血流动力学测量。用免疫印迹和实时逆转录聚合酶链反应分析心脏组织的炎症和凋亡标志物。C21显著改善收缩和舒张心室功能。瘢痕大小在C21处理的大鼠中最小。在潜在机制方面，C21减少MI诱导的Fas-配体和caspase-3在梗死周围区的表达，表明抗凋亡作用。磷酸化的p44/42和p38丝裂原活化蛋白激酶，都参与了细胞存活的调节，强烈减少MI后，但几乎完全获救的C21治疗。此外，C21降低MI诱导的血清单核细胞趋化蛋白-1和髓过氧化物酶以及心脏白细胞介素-6，白细胞介素-1 β，白细胞介素-2的表达，表明一个cardiovascular efficacy. Conclusions-Direct AT 2 receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptosis and cardiovascular mechanisms.（循环。2008; 118：2523-2532）。
Background-This study is the first to examine the effect of direct angiotensin II type 2 (AT2) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT2 receptor agonist compound 21 (C21).Methods and Results-Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1 beta, and interleukin-2 expression, suggesting an antiinflammatory effect.Conclusions-Direct AT2 receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms. (Circulation. 2008; 118: 2523-2532.)