Jayasankar Vasant, Woo Y Joseph, Bish Lawrence T, Pirolli Timothy J, Berry Mark F, Burdick Jeffrey, Bhalla Ramesh C, Sharma Ram V, Gardner Timothy J, Sweeney H Lee
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa 19104-4283, USA
Circulation. 2004 Sep 14;110(11 Suppl 1):II180-6. doi: 10.1161/01.CIR.0000138946.29375.49.
Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy.
Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (n=8) or null virus as control vector (n=8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70+/-10 versus control 56+/-12 mmHg, P<0.05; maximum dP/dt 2697+/-842 versus 1622+/-527 mmHg/sec, P<0.01; minimum dP/dt -2900+/-917 versus -1195+/-593, P<0.001). Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0+/-0.7 versus control 14.4+/-0.4 mm, P<0.001; border-zone wall thickness 1.59+/-0.11 versus control 1.28+/-0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36+/-0.87 versus control 3.89+/-1.79 microg hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5+/-0.9 versus control 43.1+/-14.9 ng of MMP-1 activity, P<0.05).
TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy. The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation.
在动物模型和人类患者中，基质金属蛋白酶（MMPs）活性增强与细胞外基质降解及缺血性心力衰竭有关。本研究评估了在缺血性心肌病大鼠模型中，通过TIMP - 1基因转移抑制MMP的作用。
大鼠接受左冠状动脉前降支结扎，并直接心肌内注射编码TIMP - 1的复制缺陷型腺病毒（n = 8）或作为对照载体的空病毒（n = 8），6周后对动物进行分析。与对照动物相比，TIMP - 1组的收缩和舒张心脏功能均得到显著保留（最大左心室[LV]压力：TIMP - 1组70±10 vs对照组56±12 mmHg，P < 0.05；最大dP/dt 2697±842 vs 1622±527 mmHg/秒，P < 0.01；最小dP/dt -2900±917 vs -1195±593，P < 0.001）。TIMP - 1组的心室几何结构得到显著保留（LV直径13.0±0.7 vs对照组14.4±0.4 mm，P < 0.001；边缘区壁厚1.59±0.11 vs对照组1.28±0.19 mm，P < 0.05），这与心肌纤维化减少有关（2.36±0.87 vs对照组3.89±1.79微克羟脯氨酸/毫克组织，P < 0.05）。TIMP - 1动物的MMP活性降低（1.5±0.9 vs对照组43.1±14.9 ng的MMP - 1活性，P < 0.05）。
TIMP - 1基因转移可抑制MMP活性，并保留缺血性心肌病中的心脏功能和几何结构。心肌纤维化的减少可能是治疗动物舒张功能改善的主要原因。TIMP - 1过表达是一个有前景的治疗靶点，有待进一步研究。
