MeCP2 regulation of cardiac fibroblast proliferation and fibrosis by down-regulation of DUSP5.
Cardiac fibrosis is a complex pathological process that includes the abnormal proliferation of cardiac fibroblasts and deposition of the extracellular matrix (ECM) proteins and collagens. Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional nuclear protein, and plays a key role in the fibrotic diseases. However, the potential role of MeCP2 in cardiac fibrosis remains unclear. We report that MeCP2 modulates cardiac fibrosis via down-regulation of dual-specificity phosphatase 5 (DUSP5), a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. MeCP2 is a critical participant in the epigenetic silencing of regulatory genes. Here, we found that down-regulation of DUSP5 in cardiac fibrosis is associated with MeCP2 over-expression. Treatment of cardiac fibroblasts with MeCP2-siRNA blocked proliferation. Knockdown of MeCP2 elevated DUSP5 expression in activated cardiac fibroblasts. Moreover, we investigated the effect of DUSP5 on the ERK1/2 activation. Our results demonstrated that MeCP2 modulates DUSP5 mediated activation of ERK1/2 in cardiac fibrosis. Taken together, these results indicated that MeCP2 acts as a key regulator of pathological cardiac fibrosis, promotes cardiac fibroblasts proliferation and fibrosis by down-regulation of DUSP5.
Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
Hui
H
Tao
Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China.
Jing-Jing
JJ
Yang
Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China.
Wei
W
Hu
Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
Kai-Hu
KH
Shi
The Second Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: zydengsy@163.com.
Zi-Yu
ZY
Deng
School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: yncs01@hotmail.com.
Jun
J
Li
D000818:Animals; D015415:Biomarkers; D009202:Cardiomyopathies / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D015870:Gene Expression; D020868:Gene Silencing; D007150:Immunohistochemistry; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
D015415:Biomarkers; D051783:Methyl-CpG-Binding Protein 2; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054637:Dual-Specificity Phosphatases; C514214:Dusp5 protein, rat
Cardiac fibrosis; Dual-specificity phosphatase 5; Methyl-CpG-binding protein 2