title: The stress-related hormone norepinephrine induced upregulation of Nix, contributing to ECM protein expression.
abstract: Organ fibrosis has been viewed as a major medical problem that leads to progressive dysfunction of the organ and eventually the death of patients. Stress-related hormone norepinephrine (NE) has been reported to exert fibrogenic actions in the injured organ. Nix plays a critical role in pressure overload-induced cardiac remodeling and heart failure through mediating cardiomyocyte apoptosis. However, cardiac remodeling also includes fibrosis. Whether Nix is involved in stress-induced fibrosis remains unclear. The present study was designed to determine the role of Nix in NE-induced NIH/3T3 fibroblasts. The results showed that Nix was upregulated and closely associated with cell proliferation, collagen and fibronectin expression in NIH/3T3 fibroblasts following NE treatment. Overexpression of Nix promoted collagen and fibronectin expression, whereas the suppression of Nix resulted in a strong reduction in collagen and fibronectin expression. Moreover, the increases in collagen and fibronectin expression induced by NE were successively increased when Nix was overexpressed and reduced when Nix was inhibited. Furthermore, we demonstrated that the PKC activation is responsible for the upregulation of Nix induced by NE. Inhibition of Nix expression with α-adrenoceptor antagonist, β-adrenoceptor antagonist or PKC inhibitor attenuated NE-induced collagen and fibronectin expression. Our data revealed that Nix is a novel mediator of NE-induced fibrosis. Thus, it would provide a new insight into the development of effective preventative measures and therapies of tissue fibrosis.
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing, 100850, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Liu
authors.forename: Xinxing
authors.initials: X
authors.lastname: Wang
authors.forename: Jingbo
authors.initials: J
authors.lastname: Gong
authors.forename: Zhusong
authors.initials: Z
authors.lastname: Mei
authors.forename: Xiujie
authors.initials: X
authors.lastname: Gao
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Lingjia
authors.initials: L
authors.lastname: Qian
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009638:Norepinephrine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D005353:Fibronectins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D047428:Protein Kinase Inhibitors; D011941:Receptors, Adrenergic; D003094:Collagen; D011493:Protein Kinase C; D009638:Norepinephrine