Chandrashekhar Y, Sen Soma, Anway Ruth, Shuros Allan, Anand Inder
Division of Cardiology, VA Medical Center and University of Minnesota, Minneapolis, Minnesota 55417, USA.
J Am Coll Cardiol. 2004 Jan 21;43(2):295-301. doi: 10.1016/j.jacc.2003.09.026.
This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling.
Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction.
A 28-day infusion of caspase inhibitor (n = 12) or vehicle (n = 9) was administered to rats immediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry.
Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to-body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI.
Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling. These findings may have important therapeutic implications in post-MI HF.
本研究旨在评估体内半胱天冬酶抑制是否能预防心肌收缩蛋白降解、改善心肌功能并减轻心室重塑。
凋亡被认为在心肌梗死（MI）后心力衰竭（HF）的发生和发展中起重要作用。然而，尚不清楚抑制凋亡是否能减轻左心室（LV）重塑并使收缩功能障碍最小化。
在大鼠前壁心肌梗死后立即给予28天的半胱天冬酶抑制剂输注（n = 12）或赋形剂（n = 9）。此外，将五只接受半胱天冬酶抑制剂的假手术大鼠与17只未治疗的假手术动物进行比较，以研究对非心肌梗死大鼠的影响。四周后研究左心室功能、重塑参数和血流动力学。使用蛋白质印迹法研究非梗死、远隔左心室心肌中的心肌半胱天冬酶3激活和肌钙蛋白I收缩蛋白裂解。使用活化半胱天冬酶阳性细胞的免疫组织化学以及TUNEL法评估凋亡。使用形态计量学估计胶原体积。
半胱天冬酶抑制降低了心肌半胱天冬酶3的激活。这伴随着心肌收缩装置的重要组成部分肌钙蛋白I的裂解减少以及凋亡心肌细胞减少。此外，半胱天冬酶抑制降低了左心室重量与体重比，减少了心肌间质胶原沉积，减轻了左心室重塑，并在心肌梗死后更好地保留了左心室收缩功能。
在心肌梗死后不久开始并持续四周的半胱天冬酶抑制可保留心肌收缩蛋白，减少收缩功能障碍，并减轻心室重塑。这些发现可能对心肌梗死后心力衰竭具有重要的治疗意义。
