Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Abstract

Secreted phospholipase A 2 -IIA (sPLA 2 -IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA 2 -IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA 2 -IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA 2 -IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA 2 -IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA 2 -IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA 2 -IIA. In conclusion, sPLA 2 -IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.

Group V secreted phospholipase A2 plays a protective role against aortic dissection

“…It seems unlikely, however, that there is a functional interplay between sPLA 2 -V and TNFa in aortic dissection, as described here. It has been shown that sPLA 2 -IIA, when transgenically overexpressed in macrophages, induces collagen deposition in the atherosclerotic plaque (66), that AT-II induces the expression of sPLA 2 -IIA in VSMCs (67), and that sPLA 2 -IIA activates the LOX-mediated collagen pathway in myofibroblasts in the process of cardiac remodeling (68). These findings may indicate some functional redundancy between sPLA 2 -V and -IIA in the context of cardiovascular disorders, although aortic dissection, arteriosclerosis, and cardiac remodeling are essentially different pathologies, and a direct comparison may not be appropriate.…”

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

“…1 ). Notably, all of these genes have been associated with myofibroblast differentiation and fibrosis (Kanisicak et al, 2016; Martin et al, 2020; Ono et al, 2018; Sun et al, 2020). Principal component analysis of the RNAseq data set revealed that at baseline fibroblast specific expression of MBNL1 causes the phenotype to transition into the same transcriptional space as non-transgenic fibroblasts subjected to MI ( Fig.…”

Exploring the Pharmacological Mechanism of the modified Chinese medicine formulas “Shenfu-Linguizhugan decoction” treating Dilated cardiomyopathy Based on Network Pharmacology

“…EGFR is a transmembrane glucoprotein that is a member of the protein kinase superfamily, and a receptor of the epidermal growth factor family, binding of the protein to a ligand induces receptor dimerization and leads to cell proliferation. Modulating EGFR transactivation and signal is a fundamental mechanism during DCM development [52,53]. Speci cally, ErbB2 signaling in cardiomyocytes is, therefore, essential for the prevention of dilated cardiomyopathy.…”