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Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress.
金属蛋白酶组织抑制剂 2 的缺乏导致左心室功能障碍加剧和不利的细胞外基质重塑响应生物力学应力。

摘要

BACKGROUND:Remodeling of the extracellular matrix (ECM) is a key aspect of myocardial response to biomechanical stress and heart failure. Tissue inhibitors of metalloproteinases (TIMPs) regulate the ECM turnover through negative regulation of matrix metalloproteinases (MMPs), which degrade the ECM structural proteins. Tissue inhibitor of metalloproteinases 2 is unique among TIMPs in activating pro-MMP2 in addition to inhibiting a number of MMPs. Given this dual role of TIMP2, we investigated whether TIMP2 serves a critical role in heart disease.
METHODS AND RESULTS:Pressure overload by transverse aortic constriction (TAC) in 8-week-old male mice resulted in greater left ventricular hypertrophy, fibrosis, dilation, and dysfunction in TIMP2-deficient (TIMP2(-/-)) compared with wild-type mice at 2 weeks and 5 weeks post-TAC. Despite lack of MMP2 activation, total collagenase activity and specific membrane type MMP activity were greater in TIMP2(-/-)-TAC hearts. Loss of TIMP2 resulted in a marked reduction of integrin β1D levels and compromised focal adhesion kinase phosphorylation, resulting in impaired adhesion of cardiomyocytes to ECM proteins, laminin, and fibronectin. Nonuniform ECM remodeling in TIMP2(-/-)-TAC hearts revealed degraded network structure as well as excess fibrillar deposition. Greater fibrosis in TIMP2(-/-)-TAC compared with wild-type TAC hearts was due to higher levels of SPARC (secreted protein acidic and rich in cysteine) and posttranslational stabilization of collagen fibers rather than increased collagen synthesis. Inhibition of MMPs including membrane type MMP significantly reduced left ventricular dilation and dysfunction, hypertrophy, and fibrosis in TIMP2(-/-)-TAC mice.
CONCLUSIONS:Lack of TIMP2 leads to exacerbated cardiac dysfunction and remodeling after pressure overload because of excess activity of membrane type MMP and loss of integrin β1D, leading to nonuniform ECM remodeling and impaired myocyte-ECM interaction.

译文

背景: 细胞外基质 (ECM) 的重塑是心肌对生物力学压力和心力衰竭反应的一个关键方面。金属蛋白酶组织抑制剂 (TIMPs) 通过负调节基质金属蛋白酶 (MMPs) 来调节细胞外基质的转换,使细胞外基质结构蛋白降解。金属蛋白酶组织抑制剂 2 在 TIMPs 中是独一无二的,除了抑制许多 MMPs 外,它还激活 pro-MMP2。鉴于 TIMP2 的双重作用,我们研究了 TIMP2 是否在心脏病中起关键作用。
方法和结果: 在 8 周龄的雄性小鼠中,通过横向主动脉缩窄 (TAC) 引起的压力超负荷导致更大的左心室肥厚、纤维化、扩张, 与 TAC 后 2 周和 5 周的野生型小鼠相比,TIMP2-deficient (TIMP2 (-/-)) 功能障碍。尽管缺乏 MMP2 活化,但总胶原酶活性和特定膜型 MMP 活性在 TIMP2 (-/-)-TAC 心脏中更高。TIMP2 的缺失导致整合素 β 1d 水平的显著降低和粘着斑激酶磷酸化的损害,导致心肌细胞对 ECM 蛋白、层粘连蛋白和纤维连接蛋白的粘附受损。TIMP2 (-/-)-TAC 心脏的非均匀 ECM 重塑揭示了退化的网络结构以及过度的纤维沉积。与野生型 TAC 相比,TIMP2 (-/-)-TAC 的纤维化程度更大是由于 SPARC (分泌的酸性蛋白和富含半胱氨酸) 水平更高和胶原纤维翻译后稳定,而不是增加胶原合成。抑制包括膜型基质金属蛋白酶在内的基质金属蛋白酶显著减少 TIMP2 (-/-)-TAC 小鼠的左心室扩张和功能障碍、肥大和纤维化。
结论: 由于膜型 MMP 的过度活动和整合素 β 1d 的丢失,缺乏 TIMP2 导致压力超负荷后心脏功能障碍和重构加剧, 导致不均匀的 ECM 重塑和受损的心肌细胞-ECM 相互作用。

Tissue inhibitor of metalloproteinases-2

重症 早期诊断的潜在标志物 临床研究术语
概述  :  

TIMP-2是一种分子量为22 kD的可溶蛋白,被认为参与了白细胞浸润、细胞损伤和细胞粘接破坏等相关过程,或者在过程中被诱导产生。TIMP-2主要由远端小管上皮细胞分泌及表达。 作用机制研究表明,TIMP-2在肾损伤发生的极早期可通过自分泌或旁分泌的方式作用于各自的受体以上调p21、p53以及p27的表达,使得p蛋白阻断周期蛋白依赖性蛋白激酶复合物(CyclD-CDK4、CyclE-CDK2)对细胞周期的促进作用,从而诱导肾小管细胞进入G1细胞周期阻滞阶段。因此,作为细胞周期阻滞的

Tissue inhibitor  

释义   组织抑制剂

例句   Tissue-inhibitor of metalloproteinase-1   

金属蛋白酶1组织抑制剂;

 

Metalloproteinases   

释义   金属蛋白酶

例句   Objective To discuss the relationship between matrix metalloproteinases and its tissue inhibitors and tissue fibrosis.

目的探讨基质金属蛋白酶及其组织抑制剂与组织纤维化的关系。


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