Tessone Ariel, Feinberg Micah S, Barbash Israel M, Reich Reuven, Holbova Radka, Richmann Michal, Mardor Yael, Leor Jonathan
Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Aviv University, Tel Hashomer, Israel.
Cardiovasc Drugs Ther. 2005 Dec;19(6):383-90. doi: 10.1007/s10557-005-5201-6.
The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline, an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction. Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium. Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction. MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced vessel density (/mm(2) +/- SEM) in the infarcted myocardium (84 +/- 16 vs. 46 +/- 9/mm(2), respectively; p < 0.05). Our work suggest that effective MMPs' inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive, non-selective inhibition of MMPs in the early healing phase after MI.
开展本研究的目的是评估强力霉素（一种有效的基质金属蛋白酶抑制剂）抑制基质金属蛋白酶（MMP）在大鼠广泛心肌梗死（MI）和左心室（LV）功能障碍模型中的临床相关性。将22只大鼠进行广泛前壁心肌梗死。此后九天开始注射强力霉素（25mg皮下注射，每日一次）或生理盐水（对照）。在心肌梗死后九天，在另一亚组（n = 8）中通过酶谱法测量强力霉素对梗死心肌和远隔心肌中MMP活性的影响。在心肌梗死后1天和30天进行超声心动图和磁共振成像（MRI）研究，以评估左心室重构和功能。4周后，将心脏固定，并进行形态计量学和组织学分析。与对照组相比，强力霉素治疗可减弱梗死心肌和远隔心肌中MMP-9和-2的活性。系列超声心动图研究表明，强力霉素未能减弱瘢痕变薄、左心室扩张和功能障碍。MRI研究表明，强力霉素损害左心室代偿性肥大。此外，与对照组相比，强力霉素降低了梗死心肌中的血管密度（/mm(2) +/- SEM）（分别为84 +/- 16与46 +/- 9/mm(2)；p < 0.05）。我们的研究表明，强力霉素对梗死心肌和远隔心肌中MMP的有效抑制并不能预防左心室重构和功能障碍，反而会损害血管生成和左心室代偿性肥大。我们的研究结果警示在心肌梗死后早期愈合阶段不要过度、非选择性地抑制MMP。
