Investigation of Extracellular Matrix Synthesis and Degradation after Myocardial Infarction.

【背景】心肌梗死（Ml）引起心肌的扩张和分裂，在其早期有时会发生心肌破裂，老年Ml中保留心肌的心肌肥大包括纤维化进展为心力衰竭。提示心肌基质金属蛋白酶（MMPs）在这些改变中起重要作用，但组织基质金属蛋白酶如MMP-1和MMP-2与这一现象的关系尚不清楚。【方法】研究血管紧张素II型1受体拮抗剂氯沙坦（losartan， LS）对大鼠急性Ml和老年Ml早期MMPs变化的影响。结扎雄性Wistar大鼠左冠状动脉产生Ml，结扎后1、2、3、4、7、14、28天取心。缺血区域用Evans蓝定义。LS （30 mg/kg/天）从Ml前1小时开始在饮用水中给予，一直持续到牺牲。通过测定心肌胶原含量来评价胶原合成，通过3h -胶原的%裂解或退化的3h -胶原和酶谱法测定心肌胶原酶和明胶酶活性来确定胶原降解。组织金属蛋白酶-1和3也用反酶技术进行了检测。测量组织髓过氧化物酶（MPO）活性以评估中性粒细胞的积累。【结果】急性心肌梗死后24小时胶原蛋白含量下降，缺血区胶原蛋白含量逐渐升高。LS对胶原蛋白含量没有影响。经酶谱分析，缺血区胶原酶活性（MMP-1 52 kDa裂解带）和明胶酶B活性（MMP-9: 92 kDa裂解带）在Ml后24小时最高，明胶酶B活性（MMP-2: 72 kDa裂解带）在Ml后6小时最高。虽然LS降低了MMP-1和MMP-2活性的峰值，但中性粒细胞来源的MMP-9活性并未受到LS的影响。【老Ml】梗死区和保留区胶原蛋白含量持续增加，直到Ml后28天。MMP-1在第7天达到峰值，然后逐渐下降。早期升高的MMP-9从第7天开始逐渐降低。从早期到第28天，TIMP-1和3持续升高。[结论]因此，建议：急性Ml早期心肌胶原代谢的改变可能受到中性粒细胞或其他炎症细胞积聚的影响，心肌梗死后细胞外基质代谢的阐明需要分为发病第3天、7天左右和心肌梗死后1 ~ 3个月3个阶段，并应考虑MMPs和TIMPs的发生率。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