Investigation of Extracellular Matrix Synthesis and Degradation after Myocardial Infarction.

[背景]心肌梗死（myocardial infarction，MI）可引起心肌扩张、分裂，早期可发生心肌破裂，而心肌肥厚包括保留心肌纤维化可导致心力衰竭。这表明，心肌基质金属蛋白酶（MMPs）在这些变化中发挥了重要作用，虽然，如何组织MMPs，如MMP-1和MMP-2与现象是未知的。[方法]观察血管紧张素Ⅱ 1型受体拮抗剂氯沙坦（Losartan，LS）对大鼠急性心肌梗死早期及陈旧性心肌梗死早期MMPs变化的影响。通过结扎雄性Wistar大鼠的左冠状动脉产生Ml，并且在结扎后1、2、3、4、7、14和28天取出心脏。用伊文思蓝法确定缺血区。从MI前1小时开始在饮用水中给予LS（30 mg/kg/天），并持续至处死。评价胶原合成 ...更多信息 d时测定心肌胶原含量，用3 H-胶原或变性3 H-胶原的裂解率和酶谱技术测定心肌胶原酶和明胶酶活性来定义降解。组织金属蛋白酶-1和3也用反向酶谱技术进行了研究。测定组织髓过氧化物酶（MPO）活性以评价中性粒细胞的蓄积。[结果]急性心肌梗死后24小时，缺血区胶原含量下降，随后逐渐升高。LS没有改变胶原含量。与对照组相比，MPO活性和胶原酶活性在Ml后24小时达到最大值，LS使这些活性的峰值略有降低。（MMP-1 52 kDa裂解条带）和明胶酶B活性在缺血区，MMP-9：92 kDa裂解条带）在MI后24小时最高，明胶酶B活性（MMP-2：72 kDa裂解条带）在MI后6小时最高。LS可降低MMP-1和MMP-2的活性峰值，但对中性粒细胞来源的MMP-9活性无明显影响。[Old心肌梗死后28天，梗死区和保留区胶原含量均持续增加。MMP-1在第7天达到高峰，然后逐渐下降。MMP-9在早期升高，从第7天开始逐渐降低。TIMP-1和TIMP-3从早期持续增加至第28天。[结论]建议：急性心肌梗死早期心肌胶原代谢的改变可能受心肌细胞或其他炎性细胞聚集的影响，心肌梗死后细胞外基质代谢的阐明需要分为3个阶段，即发病至第3天，约7天，此外，还应考虑MMPs和TIMPs的表达率。少

[Background] Myocardial infarction (Ml) causes dilatation and splitting of myocardium, then sometimes myocardial rupture will be occured during its early phase, and cardiac hypertrophy including fibrosis of -reserved myocardium progress heart failure in old Ml. It is suggested that myocardial matrix metalloproteinases (MMPs) play an important role in these alterations, although, how tissue MMPs such as MMP-1 and MMP-2 are related to the fenomenon is unknown. [Methods] We arranged this study to evaluate the effect of angiotensin II type 1 receptor antagonist, losartan (LS), on the alteration of MMPs during the early phase of acute Ml and old Ml in rats. Ml was produced by a ligation of left coronary arteries of male Wistar rat, and heart was removed 1, 2, 3, 4, 7, 14 and 28 days after the ligation. The ischemic area was defined by using Evans blue. LS (30 mg/kg/day) was administered in the drinking water from 1 hr before Ml and continued untill sacrifice. Collagen synthesis was evaluate … More d by determining myocardial collagen content, and degradation was defined by measuring myocardial collagenase and gelatinase activities using % lysis of 3H-collagen or degenerated 3H-collagen and zymographic technique. Tissue metalloproteinase -1 and 3 were also investigated by using reverse zymographic technique. Tissue myeloperoxidase (MPO) activity was measured to evaluate the accumulation of neutrophils. [Results] [Acute MI] Collagen content was decreased at 24 hr after Ml, then gradually increased in ischemic area. LS did not changed the collagen content. In cotrast, MPO activity and collagenase activity were increased maximally at 24 hr after Ml, and LS slightly decreased the peak of these activity, In the zymographic study, collagenase activity (MMP-1 52 kDa lytic band) and gelatinase B activity (MMP-9 : 92 kDa lytic band) were the highest at 24 hr after MI and gelatinase B activity (MMP-2 : 72 kDa lytic band) was highest at 6 hr after Ml in the ischemic area. Though the peaks of MMP-1 and MMP-2 activities were decreased by LS, neutrophil origin MMP-9 activities was not modified by LS.[Old Ml] Collagen contents of both infarcted and rserved area continued to increase until at 28 days after Ml. MMP-1 showed peak increase at day 7 then decreased gradually. Increased MMP-9 in early phase was gradually decresed from day 7. TIMP-1 and 3 continued to increase from ealy phase to day 28. [Conclusion) Therefore, followings were suggested ; the alteration of cardiac collagen metabolism in the early phase of acute Ml may be influenced by the accumulation of neutrophyls or other inflammatory cells, and the elucidation of extracellular matrix metabolism after myocardial infarction needs to devide into 3 phases as onset to day 3, around 7 days, and 1 to 3 month after MI.Furthermore it should be consider the rate of MMPs and TIMPs. Less