MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury.
MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury.
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DOI：
10.1016/j.jhep.2013.12.022
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发表时间：
2014-05
影响因子：
25.7
通讯作者：
Coito, Ana J.
中科院分区：
文献类型：
--
作者：
Kato, Hiroyuki;Kuriyama, Naohisa;Duarte, Sergio;Clavien, Pierre-Alain;Busuttil, Ronald W.;Coito, Ana J.
器官短缺导致脂肪变性肝脏在移植中的使用，尽管它们对缺血/再灌注损伤（IRI）的敏感性升高。基质金属蛋白酶-9（MMP-9）是一种可诱导的明胶酶，是白细胞进入炎症组织的重要介质。然而，其在脂肪变性肝IRI中的作用尚未得到证实。我们研究了MMP-9在喂食高脂饮食（HFD）的小鼠中的功能，该小鼠在部分肝IRI之前发生了约50%的肝脂肪变性，主要是大泡性脂肪变性。MMP-9−/−缺陷型脂肪变性小鼠不能表达MMP-9，这显著保护了这些小鼠免受肝脏IRI的影响。与脂肪对照组相比，MMP-9−/−脂肪性肝脏表现出显著减少的白细胞浸润、促炎细胞因子表达和肝坏死。MMP-9活性的丧失保护了血小板内皮细胞粘附分子-1（PECAM-1）的表达，PECAM-1是IRI后脂肪变性肝脏内皮细胞-细胞连接处血管完整性的调节剂。使用体外方法，我们表明，有针对性地抑制MMP-9庇护PECAM-1的细胞外部分的蛋白水解加工，并破坏白细胞迁移通过这个连接分子。此外，对再生、增殖细胞核抗原（PCNA）和组蛋白H3磷酸化（pH 3）的不同参数的评价提供了证据，证明IRI后MMP-9−/−脂肪变性肝脏中肝细胞进展到S期和有丝分裂显著增强。MMP-9活性至少部分通过PECAM-1依赖性机制破坏血管完整性，并干扰IRI后脂肪变性肝脏的再生。我们的新发现确定MMP-9是脂肪变性肝IRI的重要介质。
Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated. We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI. The inability of MMP-9−/− deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9−/− steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell–cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9−/− steatotic livers after IRI. MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI.
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DOI：
10.1111/j.1600-6143.2012.04161.x
发表时间：
2012-10
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Duarte S;Shen XD;Fondevila C;Busuttil RW;Coito AJ
通讯作者：
Coito AJ
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
7.7
作者：
Lingwal N;Padmasekar M;Samikannu B;Bretzel RG;Preissner KT;Linn T
通讯作者：
Linn T
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
影响因子：
13.5
作者：
Duarte, Sergio;Hamada, Takashi;Kuriyama, Naohisa;Busuttil, Ronald W.;Coito, Ana J.
通讯作者：
Coito, Ana J.