C1q/TNF-Related Protein 9 Inhibits Coxsackievirus B3-Induced Injury in Cardiomyocytes through NF-κB and TGF-β1/Smad2/3 by Modulating THBS1

Abstract

C1q/TNF-related protein 9 (CTRP9) is implicated in diverse cardiovascular diseases, but its role in viral myocarditis (VMC) is not well explored. This study is aimed at investigating the role and potential mechanism of CTRP9 in VMC. Herein, we found that the peripheral blood collected from children with VMC had lower CTRP9 levels than that from children who had recovered from VMC. H9c2 cardiomyocytes treated with coxsackievirus B3 (CVB3) were applied to establish a VMC model in vitro, and the expression of CTRP9 was significantly decreased in CVB3-induced H9c2 cells. The overexpression of CTRP9 attenuated CVB3-induced apoptosis, inflammation, and fibrosis reactions in H9c2 cells by promoting cell proliferation, reducing the cell apoptosis rate, and inhibiting inflammatory cytokine levels and fibrosis-related gene expression. Moreover, we found that thrombospondin 1 (THBS1) levels were increased in children with VMC, and CTRP9 negatively regulated THBS1 expression by interacting with THBS1. The downregulation of THBS1 inhibited CVB3-induced apoptosis, inflammation, and fibrosis in H9c2 cells. In addition, our mechanistic investigation indicated that the overexpression of THBS1 impaired the inhibitory effect of CTRP9 on CVB3-induced H9c2 cells. The results further revealed that the CVB3-induced NF-κB and TGF-β1/Smad2/3 signaling pathways of H9c2 cells were blocked by CTRP9 yet activated by THBS1. In conclusion, CTRP9 protected H9c2 cells from CVB3-induced injury via the NF-κB and TGF-β1/Smad2/3 signaling pathways by modulating THBS1.

Genetic landscape and immune mechanism of monocytes associated with the progression of acute-on-chronic liver failure

“…THBS1 belongs to the thrombospondin (THBS) family and has biological functions, such as promoting immune activation and enhancing inflammatory response [ 30 ]. We analyzed the expressions of potential molecules associated with the THBS1 pathway using scRNA-seq.…”

“…Studies have shown that THBS1 induces the activation and signaling of TGF-β1 and NF-κB, aggravates liver damage, promotes liver cell death, and ultimately leads to deterioration of liver function [ 27 , 31 ]. In addition, monocytes can also produce a large number of inflammatory mediators through SMAD2 and SMAD3, including dendritic cell (DC)-derived TNFSF13 and IL-18 and T cell-derived IL-2 and IL-4, which can promote the survival, proliferation, and differentiation of B cells [ 30 ]. THBS1 can induce the up-regulation of IL-1β, IL-6, and TNF-α in immune cells, among which IL-6 and TNF-α play an important role in the immune response because they not only can transmit signals but also regulate cell differentiation and apoptosis by activating inflammatory cells.…”

The landscape of circular RNA in preterm birth

“…TIMP3 is an inhibitor of MMPs and the balance of TIMPs/ MMPs is the necessary condition for maintaining the normal ECM remodeling process, while their imbalance would lead to the destruction of the internal structure of the ECM and trigger PTB (78)(79)(80). In addition, THBS1 could induce immune inflammation through downstream TGF-b and NF-kB pathways, which further facilitate the structural disruption of the maternal-fetal interface (81,82). Thus, the DECs derived from the above genes might mediate the essential processes of ECM remodeling and collagen degradation in PTB.…”

The Communal Pathogenesis, Autophagy Mechanism and Potential Therapeutic Targets in Dilated Cardiomyopathy and Viral Myocarditis

“…THBS1 encodes an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. One study showed that THBS1 induced fatal myocardial atrophy through perK-ATF4-regulated autophagy [34], and another showed that CTRP9 attenuated CVB3-induced injury in cardiomyocytes through NF-κB pathway by modulating THBS1 [35].…”