Journal of Chest Surgery

The Korean Society for Thoracic and Cardiovascular Surgery (대한심장혈관흉부외과학회)
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The Effect of Matrix Metalloproteinase Inhibitor for Left Ventricular Remodeling after Myocardial Infarction in a Rabbit Model

토끼에서 Myocardial Infarction 후 Left Ventricular Remodeling에 대한 Matrix Metalloproteinase의 차단 효과

  • Kim, Soo-Hyun (Su Thoracic and Cardiovascular Surgical Clinic) ;
  • Jung, Tae-Eun (Department of Thoracic and Cardiovascular Surgery, College of Medicine, Yeungnam University) ;
  • Hong, Geu-Ru (Division of Cardiology, Department of Internal Medicine, College of Medicine, Yeungnam University) ;
  • Han, Sung-Sae (Department of Thoracic and Cardiovascular Surgery, College of Medicine, Yeungnam University)
  • 김수현 (수 흉부외과의원) ;
  • 정태은 (영남대학교 의과대학 흉부외과학교실) ;
  • 홍그루 (영남대학교 의과대학 순환기내과) ;
  • 한승세 (영남대학교 의과대학 흉부외과학교실)
  • Published : 2007.05.05
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Abstract

Background: Matrix Metalloproteinase (MMP) inhibition has emerged as a potential therapeutic strategy for the left ventricular dilatation that occurs after myocardial infarction. This study is designed to evaluate which treatment is better for attenuating the left ventricular remodeling via MMP inhibition 1) during the early, short highly MMP producing period of the initial phase or 2) during most of the period of the initial phase after myocardial infarction. Material and Method: Myocardial infarction was induced by ligation of the left anterior descending coronary artery in rabbits. The experimental group was divided into 3 groups. The myocardial infarction only (MI only) group consisted of 7 cases. The MMP inhibitor administered for 5 days after MI (MMPI 50) group had 6 cases, and these rabbits were given MMP inhibitor for 5 days after myocardial infarction, beginning with the postoperative first day. MMP inhibitor administered for 9 days (MMPI 90) group consisted of 5 cases and these rabbits were given MMPI for 9 days the same manner as above. CG2300 was used as a selective MMPI; this is a potent MMP-2 and -9 inhibitor Two-D echocardiograms were performed on all the groups at the time of preoperative period, the post-operative 1st week, the postoperative 20 week and the postoperative 30 week, and we measured the end-diastolic dimension (EDD), the end-systolic dimension (ESD), and the ejection fraction (EF). Result: The echocardiograms generally showed postoperative left ventricular dilatation in the MI only group. The EDD was increased significantly higher in the postoperative 1 week compared to the preoperative value (p<0.05). The ESD was also increased significantly higher in the postoperative 1st week, the postoperative 20 week and the postoperative 30 week compared to the preoperative value (p<0.05). Left ventricular dilatation was noted to be less In the MMPI 9d group than in the MI only and MMPI 5d groups. In the MMPI 9d group, there was no significant change of EF postoperatively compared to the preoperative period. MMP-2 and MMP-9 were measured from the infarcted myocardial tissue at post-MI 4 weeks by performing western blotting and zymography. The changes the of protein expression and activity of MMP-2 and MMP-9 were not significant in the three MI groups and the normal heart group. Histopathologic examination revealed severe collagen deposition in the MI only group. Collagen accumulation was reduced in both the MMPI groups. The MMPI 9d group revealed an increased number of capillaries. Conclusion: Left ventricular dilatation developed rapidly after, MI from ligation of the coronary artery and MMPI attenuated the ventricular dilatation. The effect of MMPI seemed to have better a result from its usage during most of the period of the initial phase after myocardial infarction. This suggested that increased neovascularization by MMPI may also contribute to attenuation of the left ventricular remodeling.

배경: Matrix metalloproteinase (MMP) 차단은 심근경색 후 좌심실 확장에 대한 가능한 치료 전략으로 대두되고 있다. 선택적 MMP 차단제의 투여가 심근경색 후 초기 단계에 MMP가 대량으로 분비되는 짧은 기간을 차단하는 것이 좋을 것인지, 초기 전체 기간 동안 차단하여야 할 것인지를 알아보고자 하였다. 대상 및 방법: 토끼를 이용하여 기관 삽관 하에 전신 마취를 하고 흉골 정중절개한 다음 좌전 하행지 관상동맥을 결찰하여 심근경색을 만들었다. 실험군은 3군으로 나누었다. 심근경색 단독(MI only 군)군은 7예, MMP 차단제 5일 투여군(MMPI 5d 군)은 6예, MMP 차단제 9일 투여군(MMPI 9d 군)은 5예이었다. MMP 차단제로는 MMP-2와 MMP-9에 대한 선택적 차단제인 CG2300을 사용하였다. 각 군은 심장초음파도 검사를 4회 시행하였는데, 술 전, 술 후 1주, 2주 및 3주에 하였다. 검사는 2D 심초음파도를 사용하여 EDD, ESD 및 EF를 측정하였다. 술 후 4주에 희생한 토끼의 심장을 western blotting과 zymography를 하여 MMP-2와 MMP-9의 단백질과 활성의 변화를 조사하였고, 경색부위를 병리학적 조직검사를 하였다. 결과: 심초음파도 검사상, MI only군에서는 대체로 술 전에 비하여 술 후 EDD와 ESD가 증가한 추세로 좌심실이 확장하였음을 알 수 있었다. MMP 차단제 9일 투여군에서는 심근경색 단독군과 MMP 차단제 5일 투여군에 비해 좌심실의 확장이 감소한 경향을 보였다. EF는 MMP 차단제 9일 투여군에서 술 후에 술 전과 큰 변동이 없었으며, 다른 군들보다 높은 경향이었다. MMP 단백질의 발현과 활성 변화를 보면, 심근경색 단독군, MMP 차단제 5일 및 9일 투여군 등 3군을 정상 심장군과 비교하였을 때 MMP-2 단백질 발현과 활성 변화는 일어나지 않았다. 그리고 MMP-9의 단백 발현 및 활성은 검출되지 않았다. 병리학적 조직 소견을 보면 심근경색 단독군에서 심한 교원질 침착이 있었다. MMP 차단제 5일 투여군과 9일 투여군에서는 교원질 축적이 감소된 경향을 보였다. MMP 9일 투여군에서는 모세혈관의 수가 증가한 것을 볼 수 있었다. 결론: 관상동맥을 결찰하여 심근경색을 유도하면 술 후 빠른 시간 내에 심실이 확장되며 MMP 차단제를 투여할 경우 심실의 확장이 완화됨을 알 수 있었다. MMP 차단제의 효과는 초기의 대부분 기간을 차단하는 것이 좋다고 생각된다. MMP 차단제가 혈관신생을 증가시켜 심실 재형성을 완화할 수 있는 것으로 분석된다.

Keywords

References

  1. Janicki JS, Brower GL, Gardner JD, Chancey AL, Stewart JA Jr. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. Heart Failure Reviews 2004;9:33-42 https://doi.org/10.1023/B:HREV.0000011392.03037.7e
  2. Mukherjee R, Brinsa TA, Dowdy KB, et al. Myocardial infarct expansion and matrix metalloproteinase inhibition. Circulation 2003;107:618-25 https://doi.org/10.1161/01.CIR.0000046449.36178.00
  3. Brower GL, Chancey AL, Thanigaraj S, Matsubara BB, Janicki JS. Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity. Am J Physio Heart Circ Physio 2002;283:H518-25 https://doi.org/10.1152/ajpheart.00218.2000
  4. Cleutjens JPM, Kandala JC, Guarda E, Guntaka RV, Weber KT. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 1995;27:1281-92 https://doi.org/10.1016/S0022-2828(05)82390-9
  5. Lindsey ML, Gannon J, Aikawa M, et al. Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 2002;105:753-8 https://doi.org/10.1161/hc0602.103674
  6. Ducharme A, Frantz S, Aikawa M, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myo-cardial infarction. J Clin Invest 2000;106:55-62 https://doi.org/10.1172/JCI8768
  7. Jugdutt BI, Amy RWM. Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J Am Coll Cardiol 1986;7:91-102 https://doi.org/10.1016/S0735-1097(86)80265-0
  8. Darby I, Skalli O, Gabbiani G. $\alpha$-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 1990;63:21-9
  9. Spinale FH. Coker ML, Krombach RS, et al. Matrix metalloproteinase inhibition during developing congestive heart failure in pigs: effects on left ventricular geometry and function. Circ Res 1999;85:364-76 https://doi.org/10.1161/01.RES.85.4.364
  10. Rohde LE, Ducharme A, Arroyo LH, et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 1999;99:3063-70 https://doi.org/10.1161/01.CIR.99.23.3063
  11. Peterson JT, Hallak H, Johnson L, et al. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 2001;103:2303-9 https://doi.org/10.1161/01.CIR.103.18.2303
  12. White Hd, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinat of survival after recovery from myocardial infarction. Circulation 1987;76:44-51 https://doi.org/10.1161/01.CIR.76.1.44
  13. Greenwald RA. Thirty-six years in the clinic without an MMP inhibitor. What hath collagenase wrought? Ann NY Acad Sci 1999;878:413-9 https://doi.org/10.1111/j.1749-6632.1999.tb07699.x
  14. Yarbrough WM, Mukherjee R, Escobar GP, et al. Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling. Circulation 2003; 108:1753-9 https://doi.org/10.1161/01.CIR.0000093723.57673.9F
  15. Romanic AM, Burns-Kurtis CL, Gout B, Berrebi-Bertrand I, Ohlstein EH. Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci 2001;68:799-814 https://doi.org/10.1016/S0024-3205(00)00982-6
  16. Lindsey ML, Wedin K, Brown MD, et al. Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion. Circulation 2001;103:2181-7 https://doi.org/10.1161/01.CIR.103.17.2181
  17. Etoh T, Joffs C, Deschamps A, et al. Myocardial and interstitial matrix metalloproteinases activity after acute myocardial infarction in pigs. Am J Physiol Heart Circ Physiol 2001;281:987-94 https://doi.org/10.1152/ajpheart.2001.281.3.H987
  18. Sun Y, Weber KT. Infarct scar: a dynamic tissue. Cardiovasc Res 2000;46:250-6 https://doi.org/10.1016/S0008-6363(00)00032-8
  19. Lindsey ML. MMP induction and inhibition in myocaridal infarction. Heart Failure Reviews 2004;9:7-19 https://doi.org/10.1023/B:HREV.0000011390.44039.b7
  20. Creemers E, Cleutjens J, Smits J, et al. Disruption of the plasminogen gene in mice abolishes wound healing after myocardial infarction. Am J Pathol 2000;156:1865-73 https://doi.org/10.1016/S0002-9440(10)65060-2