Dataset Information

BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca²⁺]_i-TGF-?-Smad2/3 pathway.

ABSTRACT: 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, [Ca²⁺]_i, transforming growth factor beta (TGF-?) 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-? by TGF-?-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 [Ca²⁺]_i-TGF-?-Smad2/3 pathway in CFs.

SUBMITTER: Liu W

PROVIDER: S-EPMC5432493 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca<sup>2+</sup>]<sub>i</sub>-TGF-β-Smad2/3 pathway.

Liu Weili W Wang Xinxing X Mei Zhusong Z Gong Jingbo J Huang Lishuang L Gao Xiujie X Zhao Yun Y Ma Jing J Qian Lingjia L

Scientific reports 20170515 1

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 failur ...[more]

PMID: 28507335

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Project description:Fibrosis is a pronounced feature of heart disease and the result of dysregulated activation of resident cardiac fibroblasts (CFs). Recent work identified stress-induced degradation of the cytoskeletal protein βIV-spectrin as an important step in CF activation and cardiac fibrosis. Furthermore, loss of βIV-spectrin was found to depend on Ca2+/calmodulin-dependent kinase II (CaMKII). Therefore, we sought to determine the mechanism for CaMKII-dependent regulation of βIV-spectrin and CF activity. Computational screening and MS revealed a critical serine residue (S2250 in mouse and S2254 in human) in βIV-spectrin phosphorylated by CaMKII. Disruption of βIV-spectrin/CaMKII interaction or alanine substitution of βIV-spectrin Ser2250 (βIV-S2254A) prevented CaMKII-induced degradation, whereas a phosphomimetic construct (βIV-spectrin with glutamic acid substitution at serine 2254 [βIV-S2254E]) showed accelerated degradation in the absence of CaMKII. To assess the physiological significance of this phosphorylation event, we expressed exogenous βIV-S2254A and βIV-S2254E constructs in βIV-spectrin-deficient CFs, which have increased proliferation and fibrotic gene expression compared with WT CFs. βIV-S2254A but not βIV-S2254E normalized CF proliferation, gene expression, and contractility. Pathophysiological targeting of βIV-spectrin phosphorylation and subsequent degradation was identified in CFs activated with the profibrotic ligand angiotensin II, resulting in increased proliferation and signal transducer and activation of transcription 3 nuclear accumulation. While therapeutic delivery of exogenous WT βIV-spectrin partially reversed these trends, βIV-S2254A completely negated increased CF proliferation and signal transducer and activation of transcription 3 translocation. Moreover, we observed βIV-spectrin phosphorylation and associated loss in total protein within human heart tissue following heart failure. Together, these data illustrate a considerable role for the βIV-spectrin/CaMKII interaction in activating profibrotic signaling.

Dataset Information

BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca²⁺]_i-TGF-?-Smad2/3 pathway.

Publications

BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca<sup>2+</sup>]<sub>i</sub>-TGF-β-Smad2/3 pathway.

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Dataset Information

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

Publications

BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca<sup>2+</sup>]<sub>i</sub>-TGF-β-Smad2/3 pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca²⁺]_i-TGF-?-Smad2/3 pathway.