Hayakawa Yukihiro, Chandra Madhulika, Miao Wenfeng, Shirani Jamshid, Brown Joan Heller, Dorn Gerald W, Armstrong Robert C, Kitsis Richard N
Program in Molecular Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Circulation. 2003 Dec 16;108(24):3036-41. doi: 10.1161/01.CIR.0000101920.72665.58. Epub 2003 Nov 24.
Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Galpha(q) exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Galpha(q) peripartum cardiomyopathy model.
The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Galpha(q) mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3-like activity (86.5%; P<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9+/-0.3% to 0.2+/-0.1% (P<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7+/-0.1 mm; IDN-1965, 4.2+/-0.1 mm; P<0.01), fractional shortening (vehicle, 30.7+/-1.2%; IDN-1965, 38.9+/-1.0%; P<0.01), positive (vehicle, 3972+/-412; IDN-1965, 5870+/-295; P<0.01) and negative (vehicle, 2365+/-213; IDN-1965, 3413+/-201; P<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died; P<0.05).
Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Galpha(q) mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.
虽然心力衰竭期间心肌细胞凋亡的发生已有记录，但其在发病机制中的重要性尚不清楚。心脏特异性过表达Gα(q)的转基因小鼠表现出致命的围产期心肌病并伴有凋亡。为了测试凋亡是否与心力衰竭存在因果关系，我们评估了在Gα(q)围产期心肌病模型中抑制这种细胞死亡是否会改善左心室功能和生存率。
从妊娠第12天开始，通过渗透微型泵向Gα(q)小鼠皮下注射强效多聚半胱天冬酶抑制剂IDN - 1965或赋形剂，并持续至产后第14天安乐死。正如预期的那样，IDN - 1965显著抑制了心脏半胱天冬酶 - 3样活性(86.5%；P<0.01)，同时心肌细胞凋亡频率从1.9±0.3%降至0.2±0.1%(P<0.01)。接受IDN - 1965的动物在左心室舒张末期内径(赋形剂组，4.7±0.1 mm；IDN - 1965组，4.2±0.1 mm；P<0.01)、缩短分数(赋形剂组，30.7±1.2%；IDN - 1965组，38.9±1.0%；P<0.01)、正的(赋形剂组，3972±412；IDN - 1965组，5870±295；P<0.01)和负的(赋形剂组，2365±213；IDN - 1965组，3413±201；P<0.01)dP/dt方面有显著改善，并且完全抑制了死亡率(赋形剂组，20只中有6只死亡；IDN - 1965组，14只中0只死亡；P<0.05)。
通过抑制半胱天冬酶减少心肌细胞凋亡可改善妊娠Gα(q)小鼠的左心室功能和生存率。这些数据表明心肌细胞凋亡在该模型中心肌病的发病机制中起因果作用。抑制半胱天冬酶可能为心力衰竭提供一种新的治疗靶点。
