Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK

Abstract

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.

Safflower Yellow Inhibits Angiotensin II–Induced Adventitial Fibroblast Proliferation and Migration

“…Therefore, we speculate that Ang II induces the synthesis and secretion of collagens I and III via the AP1 activation pathway. Further evidence suggests that ERK1/2 signaling is primarily responsible for Ang IIinduced AP1, collagen I, and collagen III expression (29). In this study, we found that expression of the pERK1/2 protein was upregulated in the Ang II group compared to the control group.…”

<b>Docosahexaenoic acid suppresses angiotensin II-induced A7r5 vascular smooth muscle cell proliferation and migration under pulsatile pressure str</b><b>ess </b>

“…It has been reported that DHA inhibits angiotensin II-induced migration in cardiac fibroblasts by inducing reversion-inducing cysteine-rich protein with Kazal motifs (RECK) (33). Since angiotensin II inhibits RECK expression and RECK inhibits release and activation of metalloendopeptidase MMP2 (32), which triggers migration, reversal of angiotensin II-induced RECK suppression by DHA seems to be a key mechanism. DHA has also been reported to inhibit IL-1β-induced migration of rat VSMCs and suppress IL-1β-induced MMP2 as well as MMP9 via mechanisms involving DHA-induced Notch signaling pathways (4).…”

Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling

“…All data were normalized to corresponding hprt (hypoxanthine phosphoribosyltransferase) levels and analyzed using the 2 Ϫ⌬⌬Ct method. Activation of MMP2 and -9 was analyzed by immunoblotting using antibodies that detect both pro and active forms (MMP2, NB200 -114G, Novus; MMP9, M9570, Sigma) (58).…”