Autophagy inhibition of hsa-miR-19a-3p/19b-3p by targeting TGF-β R II during TGF-β1-induced fibrogenesis in human cardiac fibroblasts.
Transforming growth factor-β1 (TGF-β1) plays an important role on fibrogenesis in heart disease. MicroRNAs have exhibited as crucial regulators of cardiac homeostasis and remodeling in various heart diseases. MiR-19a-3p/19b-3p expresses with low levels in the plasma of heart failure patients. The purpose of our study is to determine the role of MiR-19a-3p/19b-3p in regulating autophagy-mediated fibrosis of human cardiac fibroblasts. We elucidate our hypothesis in clinical samples and human cardiac fibroblasts (HCF) to provide valuable basic information. TGF-β1 promotes collagen I α2 and fibronectin synthesis in HCF and that is paralleled by autophagic activation in these cells. Pharmacological inhibition of autophagy by 3-methyladenine decreases the fibrotic response, while autophagy induction of rapamycin increases the response. BECN1 knockdown and Atg5 over-expression either inhibits or enhances the fibrotic effect of TGF-β1 in experimental HCF. Furthermore, miR-19a-3p/19b-3p mimics inhibit epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) prodution and invasion of HCF. Functional studies suggest that miR-19a-3p/19b-3p inhibits autophagy of HCF through targeting TGF-β R II mRNA. Moreover, enhancement of autophagy rescues inhibition effect of miR-19a-3p/19b-3p on Smad 2 and Akt phosphorylation through TGF-β R II signaling. Our study uncovers a novel mechanism that miR-19a-3p/19b-3p inhibits autophagy-mediated fibrogenesis by targeting TGF-β R II.
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, P.R. China.
Meijuan
M
Zou
Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Fang
F
Wang
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, P.R. China.
Rui
R
Gao
Department Of Nephrology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Jingjing
J
Wu
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, P.R. China.
Yingwei
Y
Ou
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, P.R. China.
Xuguan
X
Chen
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Tongshan
T
Wang
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Xin
X
Zhou
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Wei
W
Zhu
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Ping
P
Li
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Lian-Wen
LW
Qi
Emergency Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Ting
T
Jiang
Emergency Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Weiwei
W
Wang
Emergency Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Chunyu
C
Li
Emergency Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Jun
J
Chen
Emergency Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Qifang
Q
He
Emergency Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China.
Yan
Y
Chen
D020413:3' Untranslated Regions; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D001665:Binding Sites; D015415:Biomarkers; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006351:Heart Valves / Q000378:metabolism / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
D020413:3' Untranslated Regions; D015415:Biomarkers; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II