Goussev A, Sharov V G, Shimoyama H, Tanimura M, Lesch M, Goldstein S, Sabbah H N
Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan 48202, USA.
Am J Physiol. 1998 Aug;275(2):H626-31. doi: 10.1152/ajpheart.1998.275.2.H626.
Cardiomyocyte apoptosis or programmed cell death has been shown to occur in end-stage explanted failed human hearts and in dogs with chronic heart failure (HF). We tested the hypothesis that early long-term monotherapy with an angiotensin-converting enzyme (ACE) inhibitor attenuates cardiomyocyte apoptosis in dogs with moderate HF. Left ventricular (LV) dysfunction (ejection fraction 30-40%) was produced in dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 mo of therapy with enalapril (Ena, 10 mg twice daily, n = 7) or to no therapy at all (control, n = 7). After 3 mo of therapy, dogs were euthanized and the hearts removed. Presence of nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in frozen LV sections using the immunohistochemical deoxynucleotidal transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Sections were also stained with ventricular anti-myosin antibody to identify cells of cardiocyte origin. From each dog, 80 fields (x40) were selected at random, 40 from LV regions bordering old infarcts and 40 from LV regions remote from any infarcts, for quantifying the number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes. The average number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes was significantly lower in Ena-treated dogs compared with controls (0.81 +/- 0.13 vs. 2.65 +/- 0.81, P < 0.029). This difference was due to a significantly lower incidence of cardiomyocyte nDNAf events in LV regions bordering scarred tissue (infarcts) in Ena-treated dogs compared with controls. We conclude that early long-term Ena therapy attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of cardiomyocyte apoptosis may be one mechanism by which ACE inhibitors preserve global LV function in HF.
心肌细胞凋亡或程序性细胞死亡已被证实在晚期移植的失功人类心脏以及患有慢性心力衰竭（HF）的犬类中发生。我们检验了以下假设：早期长期使用血管紧张素转换酶（ACE）抑制剂进行单一疗法可减轻中度HF犬类的心肌细胞凋亡。通过多次连续冠状动脉内微栓塞在犬类中诱发左心室（LV）功能障碍（射血分数30 - 40%）。犬类被随机分为接受依那普利治疗3个月组（依那普利，每日两次，每次10 mg，n = 7）或不接受任何治疗组（对照组，n = 7）。治疗3个月后，对犬类实施安乐死并取出心脏。使用免疫组织化学脱氧核苷酸转移酶介导的dUTP - 地高辛配基缺口末端标记（TUNEL）方法，在冷冻的LV切片中评估凋亡标志物核DNA片段化（nDNAf）的存在情况。切片还用心室抗肌球蛋白抗体染色以识别心肌细胞来源的细胞。从每只犬类中随机选择80个视野（×40），其中40个来自与陈旧性梗死灶相邻的LV区域，40个来自远离任何梗死灶的LV区域，用于量化每1000个心肌细胞中心肌细胞核DNA片段化事件的数量。与对照组相比，依那普利治疗的犬类中每1000个心肌细胞中心肌细胞核DNA片段化事件的平均数量显著更低（0.81±0.13对2.65±0.81，P < 0.029）。这种差异是由于与对照组相比，依那普利治疗的犬类中与瘢痕组织（梗死灶）相邻的LV区域中心肌细胞核DNA片段化事件的发生率显著更低。我们得出结论，早期长期依那普利治疗可减轻中度HF犬类的心肌细胞凋亡。心肌细胞凋亡的减轻可能是ACE抑制剂在HF中维持整体LV功能的一种机制。
