Yamani Mohamad H, Starling Randall C, Cook Daniel J, Tuzcu E Murat, Abdo Ashraf, Paul Philip, Powell Kimerly, Ratliff Norman B, Yu Yang, McCarthy Patrick M, Young James B
Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Circulation. 2003 Oct 7;108(14):1724-8. doi: 10.1161/01.CIR.0000087604.27270.5B. Epub 2003 Sep 15.
Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy.
We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69).
This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.
基质金属蛋白酶（MMP）-2和MMP-9已被证明在出血性卒中进展中起作用。我们推测供体脑出血（ICH）与移植前金属蛋白酶的激活有关，而金属蛋白酶的激活在随后移植血管病变的发展中起关键作用。
我们评估了20例来自ICH供体的受体和20例来自创伤供体的受体在移植前供体脾淋巴细胞中以及移植后1周心脏活检组织中MMP-2和MMP-9的mRNA表达。患者接受了系列冠状动脉血管内超声检查，并在1年时对心肌间质纤维化进行了定量分析。除ICH组供体年龄增加外，两组基线特征相似。与创伤组相比，ICH组心脏活检组织中MMP-2（17倍，P<0.0001）和MMP-9（20倍，P<0.0001）的表达显著增加。此外，ICH组供体脾淋巴细胞中MMP-2的mRNA表达增加1.8倍（P=0.016），MMP-9的mRNA表达增加1.7倍（P=0.015），提示移植前存在金属蛋白酶的全身激活。1年时，ICH组心肌纤维化增加，冠状动脉病变加速。通过多变量回归分析发现，MMP-9与血管病变风险增加相关，且独立于供体年龄（比值比，2.41；P=0.01；95%可信区间，1.24至4.69）。
这是首篇描述脑出血供体中MMP-2和MMP-9全身激活以及随后同种异体移植血管病变发展的报告。
