RETRACTED ARTICLE: Amphiregulin enhances cardiac fibrosis and aggravates cardiac dysfunction in mice with experimental myocardial infarction partly through activating EGFR-dependent pathway

Abstract

Cardiac fibrosis (CF), a main process of ventricular remodeling after myocardial infarction (MI), plays a crucial role in the pathogenesis of heart failure (HF) post-MI. It is known that amphiregulin (AR) is involved in fibrosis of several organs. However, the expression of AR and its role post-MI are yet to be determined. This study aimed to investigate the impact of AR on CF post-MI and related mechanisms. Significantly upregulated AR expression was evidenced in the infarct border zone of MI mice in vivo and the AR secretion was enhanced in macrophages, but not in cardiac fibroblasts. In vitro, treatment with AR increased cardiac fibroblast migration, proliferation and collagen synthesis, and upregulated the expression of epidermal growth factor receptor (EGFR) and the downstream genes such as Akt, ERK1/2 and Samd2/3 on cardiac fibroblasts. All these effects could be abrogated by pretreatment with a specific EGFR inhibitor. To verify the functions of AR in MI hearts, lentivirus-AR-shRNA and negative control vectors were delivered into the infarct border zone. After 28 days, knock-down of AR increased the survival rate and improved cardiac function, while decreasing the extent of myocardial fibrosis of MI mice. Moreover, EGFR and the downstream genes were significantly downregulated in lentivirus-AR-shRNA treated MI mice. Our results thus indicate that AR plays an important role in promoting CF after MI partly though activating the EGFR pathway. Targeting AR might be a novel therapeutic option for attenuating CF and improve cardiac function after MI.

Airway Basal Cells show a dedifferentiated KRT17highPhenotype and promote Fibrosis in Idiopathic Pulmonary Fibrosis

“…Generally, the role of EGFR ligand family members in fibrosis has been studied mainly in other organs with sometimes conflicting results. However, amphiregulin has been most consistently shown profibrotic effects in models of liver, kidney and heart fibrosis [37][38][39][40] . In the lung, amphiregulin was proposed as a mediator of TGFB1 mediated pulmonary fibrosis in the triple transgenic mouse model 41 2), markers of epithelial cells senescence such as GDF15 45 , and the EGFR ligands AREG and HBEGF in IPF-ABCs.…”

SRV2 promotes mitochondrial fission and Mst1-Drp1 signaling in LPS-induced septic cardiomyopathy

“…At the molecular level, accumulation of Drp1 and Factin assembly initiate mitochondrial fission [44]. Drp1 forms a ring structure that causes mitochondrial contraction, and F-actin provides an adhesive force that helps Drp1 to complete mitochondrial contraction [45,46]. Notably, SRV2 promotes polarized actin cable assembly, facilitates actin turnover [47], and enhances F-actin synthesis.…”

Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress

“…Basal phosphorylation of ERK1/2 is enhanced by RKIP -knockout and not changed by TAC. Recent reports demonstrate that the Raf-MEK-ERK signaling pathway plays a differential role during the time course of cardiac remodeling: increased phosphorylation and activation of ERK1/2 in early stage promotes cardiomyocyte hypertrophy and cardiac remodelling but in later stages decreased phosphorylation and downregulation of ERK1/2 increases myocyte apoptosis leading to LV dilatation and heart failure [ 14 , 24 – 26 ]. Thus, systemic RKIP -deficiency ameliorates cardiac remodeling activating Raf-MEK-ERK signaling pathway during 5 weeks of pressure-overload.…”