Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK.
Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK.
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DOI：
10.1016/j.yjmcc.2013.09.015
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发表时间：
2013-12
影响因子：
5
通讯作者：
Chandrasekar, Bysani
中科院分区：
文献类型：
--
作者：
Siddesha, Jalahalli M.;Valente, Anthony J.;Sakamuri, Siva S. V. P.;Yoshida, Tadashi;Gardner, Jason D.;Somanna, Naveen;Takahashi, Chiaki;Noda, Makoto;Chandrasekar, Bysani
基质金属蛋白酶或MMPs的持续诱导和激活以及细胞外基质的破坏和沉积是心肌纤维化的特征。具有Kazal基序的逆转诱导富含半胱氨酸蛋白(RECK)是一种独特的膜锚定内源性基质金属蛋白酶抑制因子。我们假设，在体内和体外，与心脏纤维化相关的血管紧张素II(Ang II)升高对MMPs和RECK具有不同的调节作用。雄性C57BL/6小鼠连续注射血管紧张素转换酶II 2周，可导致心肌纤维化，MMP2、7、9、14、Ia1、IIIa1表达增加。然而，RECK的表达明显受到抑制。这些作用可通过与血管紧张素II 1型受体(AT1)拮抗剂氯沙坦共同处理而被抑制。在体外，Ang II通过AT1/NOX4依赖的ERK/Sp1激活抑制成年小鼠心脏成纤维细胞RECK的表达，而通过激活NF-κB、AP-1和/或Sp1诱导MMP2、7和9的表达。此外，虽然RECK的强制表达被抑制，但它的敲除增强了Ang II诱导的CF迁移。值得注意的是，RECK过表达降低了Ang II诱导的MMP2、9和14的激活，但促进了Ia1和IIIa1胶原的表达和可溶性胶原的释放。这些结果首次证明，Ang II抑制RECK，但在体内和体外诱导MMPs，而RECK过表达抑制Ang II在体外诱导的MMPs活化和CFs迁移。体内上调RECK表达的策略有可能减弱持续的基质金属蛋白酶表达，并减缓高血压心脏病的纤维化和不良重塑。
Sustained induction and activation of matrixins (matrix metalloproteinases or MMPs), and the destruction and deposition of extracellular matrix (ECM), are the hallmarks of cardiac fibrosis. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is a unique membrane-anchored endogenous MMP inhibitor. We hypothesized that elevated angiotensin II (Ang II), which is associated with fibrosis in the heart, differentially regulates MMPs and RECK both in vivo and in vitro. Continuous infusion of Ang II into male C57Bl/6 mice for 2 weeks resulted in cardiac fibrosis, with increased expressions of MMPs 2, 7, 9 and 14, and of collagens Ia1 and IIIa1. The expression of RECK, however, was markedly suppressed. These effects were inhibited by co-treatment with the Ang II type 1 receptor (AT1) antagonist losartan. In vitro, Ang II suppressed RECK expression in adult mouse cardiac fibroblasts (CF) via AT1/Nox4-dependent ERK/Sp1 activation, but induced MMPs 2, 7 and 9 via NF-κB, AP-1 and/or Sp1 activation. Further, while forced expression of RECK inhibits, its knockdown potentiates Ang II-induced CF migration. Notably, RECK overexpression reduced Ang II-induced MMPs 2, 9 and 14 activation, but enhanced collagens Ia1 and IIIa1 expression and soluble collagen release. These results demonstrate for the first time that Ang II suppresses RECK, but induces MMPs both in vivo and in vitro, and RECK overexpression blunts Ang II induced MMP activation and CF migration in vitro. Strategies that upregulate RECK expression in vivo have the potential to attenuate sustained MMP expression, and blunt fibrosis and adverse remodeling in hypertensive heart diseases.
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DOI：
10.1186/1755-1536-5-15
发表时间：
2012-09-03
期刊：
Fibrogenesis & tissue repair
影响因子：
--
作者：
Fan D;Takawale A;Lee J;Kassiri Z
通讯作者：
Kassiri Z
影响因子：
4.8
作者：
Chang, HC;Liu, LT;Hung, WC
通讯作者：
Hung, WC
影响因子：
37.8
作者：
Lindsey, ML;Escobar, P;Spinale, FG
通讯作者：
Spinale, FG
DOI：
10.1152/ajprenal.00019.2008
发表时间：
2008-09-01
影响因子：
4.2
作者：
Gonzalez-Villalobos, Romer A.;Seth, Dale M.;Navar, L. G.
通讯作者：
Navar, L. G.
DOI：
10.1073/pnas.0508085102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Lee, JG;Dahi, S;Sarkar, R
通讯作者：
Sarkar, R