| Co-Investigator(Kenkyū-buntansha) |
HIRAYAMA Hiroyoshi Medical Institute of Bioregulation Kyushu University Clinical and Research, 生体防御医学研究所, 医員
YANO Kenichi Medical Institute of Bioregulation Kyushu University Research Associate, 生体防御医学研究所, 助手 (60230281)
MAKINO Naoki Medical Institute of Bioregulation Kyushu University Associate Professor, 生体防御医学研究所, 助教授 (60157170)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
[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
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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
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