Sabbah H N, Sharov V G, Gupta R C, Todor A, Singh V, Goldstein S
Department of Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA.
J Am Coll Cardiol. 2000 Nov 1;36(5):1698-705. doi: 10.1016/s0735-1097(00)00913-x.
The purpose of this study was to determine if therapy with beta-blockade is associated with reduced cardiomyocyte apoptosis.
Chronic treatment with beta-adrenergic blocking agents has been shown to improve left ventricular (LV) ejection fraction and attenuate progressive LV remodeling in heart failure (HF). Cardiomyocyte apoptosis has also been shown to occur in the failing heart.
Moderate HF was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to three months therapy with metoprolol (MET, 25 mg twice daily, n = 7) or to no therapy at all (n = 7). At the end of three months, dogs were sacrificed, and nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in LV tissue using the TUNEL assay. The number of cardiomyocytes with positive nDNAf labeling per 1,000 was quantified in LV regions bordering old infarcts and in regions remote from infarcts. Endonuclease activity and expression of the antiapoptotic protein Bcl-2 and the proapoptotic proteins Bax and caspase-3 were also evaluated in LV tissue.
The number of nDNAf events per 1,000 cardiomyocytes was lower in dogs treated with MET compared with untreated dogs with HF in the border regions (0.35 +/- 0.07 vs. 5.32 +/- 0.77, p < 0.001) as well as the remote regions (0.07 +/- 0.05 vs. 0.39 +/- 0.12, p < 0.05). Endonuclease activity was also significantly lower in MET-treated compared with untreated dogs (25 +/- 3 vs. 37 +/- 2 ng [3H]DNA rendered soluble/min/mg protein). Western blotting for Bcl-2, Bax and caspase-3 showed increased expression of Bcl-2, decreased expression of caspase-3 and no change in Bax in MET-treated compared with untreated dogs.
Chronic therapy with MET attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of ongoing cardiomyocyte loss through apoptosis may be one mechanism through which beta-blockers elicit their benefits in HF.
本研究旨在确定β受体阻滞剂治疗是否与心肌细胞凋亡减少相关。
β肾上腺素能阻滞剂的长期治疗已被证明可改善左心室（LV）射血分数，并减轻心力衰竭（HF）时左心室的进行性重塑。心肌细胞凋亡也已被证明发生在衰竭心脏中。
通过冠状动脉内微栓塞在14只犬中诱发中度HF。将犬随机分为接受美托洛尔治疗三个月组（MET，25mg，每日两次，n = 7）或不接受任何治疗组（n = 7）。在三个月结束时，处死犬，使用TUNEL法评估左心室组织中作为凋亡标志物的核DNA片段化（nDNAf）。对每1000个具有阳性nDNAf标记的心肌细胞数量在与陈旧性梗死相邻的左心室区域和远离梗死的区域进行定量。还评估了左心室组织中的核酸内切酶活性以及抗凋亡蛋白Bcl-2和促凋亡蛋白Bax及半胱天冬酶-3的表达。
与未治疗的HF犬相比，接受MET治疗的犬在边界区域每1000个心肌细胞中的nDNAf事件数量更低（0.35±0.07对5.32±0.77，p<0.001）以及在远离区域（0.07±0.05对0.39±0.12，p<0.05）。与未治疗的犬相比，接受MET治疗的犬的核酸内切酶活性也显著更低（25±3对37±2ng [3H]DNA可溶/分钟/毫克蛋白）。与未治疗的犬相比，接受MET治疗的犬的Bcl-2、Bax和半胱天冬酶-3的蛋白质免疫印迹显示Bcl-2表达增加，半胱天冬酶-3表达降低，Bax无变化。
MET的长期治疗可减轻中度HF犬的心肌细胞凋亡。通过凋亡减轻持续的心肌细胞丢失可能是β受体阻滞剂在HF中发挥益处的一种机制。
