title: Fibrillar Type I Collagen Enhances the Differentiation and Proliferation of Myofibroblasts by Loweringα2β1 Integrin Expression in Cardiac Fibrosis.
abstract: Many studies have shown thatα2β1 integrin plays an important role in the development of cardiac fibrosis. However, the mechanism of howα2β1 integrin regulates the differentiation and proliferation of myofibroblasts in cardiac fibrosis through fibrillar collagen (FC) remains uncertain. We established that FC mimicked the 3-dimensional extracellular matrix (ECM) of fibroblasts from post-myocardial infarction (MI) patients in vivo. This allowed us to explore the differentiation and proliferation of cardiac fibroblasts on FC. Here, we report that low expression ofα2β1 integrin increased protein kinase B (AKT) activation andα-smooth muscle actin (α-SMA) expression. This occurred due to the instability of phosphatase and tensin homolog (PTEN) in myofibroblasts on FC. We also demonstrated that FC reduced protein phosphatase type 2A (PP2A) activity of myofibroblasts, which was coincident with lowα2β1 integrin expression and activation of AKT, but not mitogen-activated protein kinase (ERK). In addition, knock-down of bothβ1 integrin and PP2A in fibroblasts promoted differentiation and proliferation via AKT activation and increasedα-SMA expression. In summary, our study demonstrated that lowα2β1 integrin expression regulated its downstream targets PTEN and AKT via crosstalk with PP2A, a critical cell signaling pathway that permits aberrant differentiation and proliferation of myofibroblasts on FC.
authors.affiliation: Department of Cardiology, Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Cardiology, Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Cardiology, Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Cardiology, Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Junhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Di
authors.identifier: 0000-0003-1753-7616
authors.initials: D
authors.lastname: Xu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000494:pharmacology*; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D038982:Integrin alpha2beta1; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase