BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways

Xiuxia Qu, Ying Liu, Dayan Cao, L. Jinghai Chen, Zhuo Liu, Hongrui Ji, Yuwen Chen, Wenjun Zhang, Ping Zhu, Deyong Xiao, Xiaohui Li, Weinian Shou, Hanying Chen

Research output: Contribution to journalArticle

Abstract

Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor-superfamily that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro. Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- A nd STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.

Original languageEnglish (US)
Pages (from-to)19877-19888
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number52
DOIs
StatePublished - Jan 1 2019

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STAT3 Transcription Factor
Bone Morphogenetic Proteins
Chemical activation
Activin Receptors
Transgenic Mice
Cardiac Myocytes
Type II Activin Receptors
Fibrosis
Genes
Heart Injuries
Myosin Heavy Chains
Transforming Growth Factors
Tamoxifen
Growth and Development
Isoproterenol
Intercellular Signaling Peptides and Proteins
Heart Failure
Apoptosis
Peptides
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways. / Qu, Xiuxia; Liu, Ying; Cao, Dayan; Chen, L. Jinghai; Liu, Zhuo; Ji, Hongrui; Chen, Yuwen; Zhang, Wenjun; Zhu, Ping; Xiao, Deyong; Li, Xiaohui; Shou, Weinian; Chen, Hanying.

In: Journal of Biological Chemistry, Vol. 294, No. 52, 01.01.2019, p. 19877-19888.

Research output: Contribution to journalArticle

Qu, X, Liu, Y, Cao, D, Chen, LJ, Liu, Z, Ji, H, Chen, Y, Zhang, W, Zhu, P, Xiao, D, Li, X, Shou, W & Chen, H 2019, 'BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways', Journal of Biological Chemistry, vol. 294, no. 52, pp. 19877-19888. https://doi.org/10.1074/jbc.RA119.010943
Qu, Xiuxia ; Liu, Ying ; Cao, Dayan ; Chen, L. Jinghai ; Liu, Zhuo ; Ji, Hongrui ; Chen, Yuwen ; Zhang, Wenjun ; Zhu, Ping ; Xiao, Deyong ; Li, Xiaohui ; Shou, Weinian ; Chen, Hanying. / BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 52. pp. 19877-19888.
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