Leri A, Liu Y, Li B, Fiordaliso F, Malhotra A, Latini R, Kajstura J, Anversa P
Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.
Am J Pathol. 2000 May;156(5):1663-72. doi: 10.1016/S0002-9440(10)65037-7.
To determine whether up-regulation of AT(1) and AT(2) receptors occurred in hypertrophied myocytes after infarction and whether AT(2) played a role in stretch-mediated apoptosis, left ventricular myocytes were dissociated from the surviving portion of the wall 8 days after coronary occlusion and cardiac failure in rats. Control cells were obtained from sham-operated animals. Myocytes were stretched in an equibiaxial stretch apparatus and angiotensin II (Ang II) formation and cell death were measured 3 and 12 hours later. AT(1) and AT(2) proteins were evaluated in freshly isolated myocytes and after stretch. The effects of AT(1) and AT(2) antagonists on stretch-induced Ang II synthesis and apoptosis were also established. Myocardial infarction increased AT(1) and AT(2) in myocytes and stretch further up-regulated these receptors. Ang II levels were higher in postinfarcted myocytes and this peptide increased with the duration of stretch in both groups of cells. Similarly, apoptosis increased with time in control and postinfarcted myocytes. Absolute values of Ang II and apoptosis were greater in myocytes from infarcted hearts at 3 and 12 hours after stretch. Addition of AT(1) blocker to cultures inhibited stretch-activated apoptosis in both myocyte populations as well as the generation of Ang II in postinfarcted myocytes. In contrast, AT(2) antagonists had no impact on these cellular events. In conclusion, Ang II stimulated cell death through AT(1) receptor activation, whereas ligand binding to AT(2) receptor did not alter Ang II concentration and apoptosis in normal and postinfarcted hypertrophied myocytes.
为了确定梗死心肌肥厚细胞中是否存在AT(1)和AT(2)受体上调，以及AT(2)是否在牵张介导的细胞凋亡中发挥作用，在大鼠冠状动脉闭塞并发生心力衰竭8天后，从左心室壁存活部分分离出心肌细胞。对照细胞取自假手术动物。将心肌细胞置于双轴牵张装置中进行牵张，3小时和12小时后检测血管紧张素II（Ang II）生成及细胞死亡情况。对新鲜分离的心肌细胞以及牵张后的细胞进行AT(1)和AT(2)蛋白评估。还确定了AT(1)和AT(2)拮抗剂对牵张诱导的Ang II合成及细胞凋亡的影响。心肌梗死增加了心肌细胞中的AT(1)和AT(2)，牵张进一步上调了这些受体。梗死心肌细胞中的Ang II水平更高，且该肽在两组细胞中均随牵张时间延长而增加。同样，对照和梗死心肌细胞中的细胞凋亡均随时间增加。牵张后3小时和12小时，梗死心脏来源的心肌细胞中Ang II和细胞凋亡的绝对值更大。向培养物中添加AT(1)阻滞剂可抑制两个心肌细胞群体中牵张激活的细胞凋亡以及梗死心肌细胞中Ang II的生成。相比之下，AT(2)拮抗剂对这些细胞事件没有影响。总之，Ang II通过激活AT(1)受体刺激细胞死亡，而在正常和梗死心肌肥厚细胞中，配体与AT(2)受体结合不会改变Ang II浓度及细胞凋亡。
