TY - JOUR
T1 - BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways
AU - Qu, Xiuxia
AU - Liu, Ying
AU - Cao, Dayan
AU - Chen, L. Jinghai
AU - Liu, Zhuo
AU - Ji, Hongrui
AU - Chen, Yuwen
AU - Zhang, Wenjun
AU - Zhu, Ping
AU - Xiao, Deyong
AU - Li, Xiaohui
AU - Shou, Weinian
AU - Chen, Hanying
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grants R01HL145060, R01HL81092, P01HL134599, and P01HL85098 (to W. S.), a grant from the Indiana University Showalter Research Trust Fund (to H. C.), and National Science Foundation China Projects of International Cooper-ation and Exchanges Grant 81720102004 and National Science Founda-tion China Grants 81570279 and 81974019 (to P. Z.) to support P. Z. as a visiting Scholar in Shou Lab. The authors declare that they have no con-flicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 Kollenstart et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2019/12/27
Y1 - 2019/12/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077296346&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA119.010943
DO - 10.1074/jbc.RA119.010943
M3 - Article
C2 - 31712309
AN - SCOPUS:85077296346
SN - 0021-9258
VL - 294
SP - 19877
EP - 19888
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -