EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-κB andMKK7/JNK/AP-1 signaling

Abstract

The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN), and the pleiotropic proinflammatory cytokine interleukin (IL)-18, play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNKdependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-κB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-κB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNA. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

“…Also significantly more highly phosphorylated in R9C hearts was a previously uncharacterized T187 site in EMMPRIN (BSG/ CD147), an extracellular metalloprotease-inducing member of the Ig superfamily, consistent with its role in inflammatory processes in cardiac remodeling (14). In addition, the S2 phosphosite on transcription factor MAX (Myc-associated factor X) (15), a positive regulator of cardiac alpha-myosin heavy-chain gene expression in cardiomyocytes, was significantly altered in R9C mice.…”

Regulation of invadopodia formation and activity by CD147

“…Among the best characterized functions of CD147 is induction of MMPs, including MT1-MMP Yan et al, 2005). The exact mechanisms by which CD147 induces MMPs is not known, but current evidence indicates that homophilic CD147 interactions mediate this induction (Sun and Hemler, 2001;Tang et al, 2004b) and result in various downstream signaling events that promote MMP synthesis and other activities (Ghatak et 1998; Tang et al, 2008;Venkatesan et al, 2010;Yang et al, 2006). In agreement with earlier studies, we demonstrated that upregulation or downregulation of CD147 increases or decreases, respectively, the levels of MT1-MMP and invasiveness.…”

Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation

“…These results suggest that the main function of Bsg in CyPA-mediated vascular remodeling and PH is not in the inflammatory cells but in the pulmonary vascular Bsg. Bsg induces Rac-1-dependent expression of inflammatory cytokines 44 and promotes VSMC proliferation. 45 These reports support our notion that the secretion of inflammatory cytokines was augmented by cooperative interaction between extracellular CyPA and Bsg in the pulmonary vasculature.…”