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

Abstract

Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β 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 α-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- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.

• Authors: Xiuxia Qu, Ying Liu, Dayan Cao, Jinghai Chen, Zhuo Liu, Hongrui Ji, Yuwen Chen, Wenjun Zhang, Ping Zhu, Deyong Xiao, Xiaohui Li, Weinian Shou, Hanying Chen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 52 Pg. 19877-19888 (12 27 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 31712309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Qu et al.

Chemical References

• Adrenergic beta-3 Receptor Agonists
• BMP10 protein, human
• Bone Morphogenetic Proteins
• Recombinant Proteins
• STAT3 Transcription Factor
• Smad Proteins
• Isoproterenol

Topics

• Adrenergic beta-3 Receptor Agonists (pharmacology)
• Animals
• Apoptosis (drug effects)
• Bone Morphogenetic Proteins (genetics, metabolism)
• Extracellular Matrix (metabolism)
• Heart (drug effects)
• Humans
• Isoproterenol (pharmacology)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Transgenic
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (cytology, metabolism)
• Recombinant Proteins (biosynthesis, isolation & purification, pharmacology)
• STAT3 Transcription Factor (deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• Smad Proteins (metabolism)