ABSTRACT
BACKGROUND: Acute myocardial infarction (AMI)-induced excessive myocardial fibrosis exaggerates cardiac dysfunction. However, serum Wnt2 or Wnt4 level in AMI patients, and the roles in cardiac fibrosis are largely unkown. METHODS: AMI and non-AMI patients were enrolled to examine serum Wnt2 and Wnt4 levels by ELISA analysis. The AMI patients were followed-up for one year. MI mouse model was built by ligation of left anterior descending branch (LAD). FINDINGS: Serum Wnt2 or Wnt4 level was increased in patients with AMI, and the elevated Wnt2 and Wnt4 were correlated to adverse outcome of these patients. Knockdown of Wnt2 and Wnt4 significantly attenuated myocardial remodeling and cardiac dysfunction following experimental MI. In vitro, hypoxia enhanced the secretion and expression of Wnt2 and Wnt4 in neonatal rat cardiac myocytes (NRCMs) or fibroblasts (NRCFs). Mechanistically, the elevated Wnt2 or Wnt4 activated ß-catenin /NF-κB signaling to promote pro-fibrotic effects in cultured NRCFs. In addition, Wnt2 or Wnt4 upregulated the expression of these Wnt co-receptors, frizzled (Fzd) 2, Fzd4 and (low-density lipoprotein receptor-related protein 6 (LRP6). Further analysis revealed that Wnt2 or Wnt4 activated ß-catenin /NF-κB by the co-operation of Fzd4 or Fzd2 and LRP6 signaling, respectively. INTERPRETATION: Elevated Wnt2 and Wnt4 activate ß-catenin/NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 in fibroblasts, which contributes to adverse outcome of patients with AMI, suggesting that systemic inhibition of Wnt2 and Wnt4 may improve cardiac dysfunction after MI.
Subject(s)
Frizzled Receptors/metabolism , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Myocardial Infarction/metabolism , Up-Regulation , Wnt2 Protein/blood , Wnt4 Protein/blood , Aged , Animals , Case-Control Studies , Disease Models, Animal , Female , Gene Knockdown Techniques , Humans , Male , Mice , Middle Aged , Myocardial Infarction/blood , NF-kappa B/metabolism , Rats , Signal Transduction , Wnt2 Protein/genetics , Wnt2 Protein/metabolism , Wnt4 Protein/genetics , Wnt4 Protein/metabolismABSTRACT
OBJECTIVE: To observe the expression of Wnt2 in the breast cancer cells (MDA-MB-231, ZR-75-30 and MCF-7) and tissues, and analyze the correlation of Wnt2 expression with CA-153 in the sera of patients with breast cancer. METHODS: The expression of Wnt2 at both mRNA and protein levels was measured respectively by real-time fluorescent quantitative PCR and Western blotting in the three human breast cancer cell lines. In addition, the immunohistochemistry (IHC) was applied to detect the expression of Wnt2 in 5 corresponding tissues adjacent to cancer, 9 breast carcinoma in situ and 9 invasive breast cancer; ELISA was used to detect Wnt2 and electrochemiluminescence immunoassay was used to detect CA-153 in the sera of 15 normal women and 30 patients with breast cancer. Furthermore, we collected complete clinicopathological data from the participating subjects, and analyzed their relationships with serum Wnt2 levels. RESULTS: The mRNA and protein of Wnt2 were negative in the three human breast cancer cells, while Wnt2 in the epithelial and interstitial cells of breast cancer tissues was significantly higher than that in normal tissues (P<0.05). The expression levels of Wnt2 and CA-153 in the sera of patients with breast cancer were higher than those in normal women (P<0.05), and Wnt2 levels in the sera of breast cancer patients were positively correlated with serum CA-153 levels. CONCLUSION: Simultaneous tests of Wnt2 and CA-153 levels in the serum may help the diagnostic screening of breast cancer.
