BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca2+]i-TGF-β-Smad2/3 pathway

• Published in: Scientific reports 2017-05, Vol.7 (1), p.1906-13, Article 1906
• Main Authors: Liu, Weili, Wang, Xinxing, Mei, Zhusong, Gong, Jingbo, Huang, lishuang, Gao, Xiujie, Zhao, Yun, Ma, Jing, Qian, Lingjia
• Format: Article
• Language: English
• Subjects: 13/2; 13/31; 13/51; 38/109; 631/443/592/1540; 692/4019/592; 82/80; Animals; Apoptosis; Blood Pressure; Calcium; Calcium (intracellular); Cardiomyocytes; Cell Proliferation; Disease Models, Animal; Extracellular Matrix; Fibroblasts; Fibronectin; Fibrosis; Heart diseases; Heart Diseases - etiology; Heart Diseases - metabolism; Heart Diseases - pathology; Heart failure; Humanities and Social Sciences; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; multidisciplinary; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myofibroblasts - metabolism; Myofibroblasts - pathology; Neonates; Norepinephrine; Overexpression; Pressure; Protein kinase C; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Rodents; Science; Science (multidisciplinary); Signal Transduction; siRNA; Smad2 protein; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01936-5

Fibrosis is an important, structurally damaging event that occurs in pathological cardiac remodeling, leading to cardiac dysfunction. BNIP3L is up-regulated in pressure overload-induced heart failure and has been reported to play an important role in cardiomyocyte apoptosis; however, its involvement in cardiac fibroblasts (CFs) remains unknown. We prove for the first time that the expression of BNIP3L is significantly increased in the CFs of rats undergoing pressure overload-induced heart failure. Furthermore, this increased BNIP3L expression was confirmed in cultured neonatal rat CFs undergoing proliferation and extracellular matrix (ECM) protein over-expression that was induced by norepinephrine (NE). The overexpression or suppression of BNIP3L promoted or inhibited NE-induced proliferation and ECM expression in CFs, respectively. In addition, [Ca 2+ ] i , transforming growth factor beta (TGF-β) and the nuclear accumulation of Smad2/3 were successively increased when BNIP3L was overexpressed and reduced when BNIP3L was inhibited. Furthermore, the down-regulation of TGF-β by TGF-β-siRNA attenuated the increase of BNIP3L-induced fibronectin expression. We also demonstrated that the increase of BNIP3L in CFs was regulated by NE-AR-PKC pathway in vitro and in vivo . These results reveal that BNIP3L is a novel mediator of pressure overload-induced cardiac fibrosis through the [Ca 2+ ] i -TGF-β-Smad2/3 pathway in CFs.