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p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart.

Publication ,  Journal Article
Yokota, T; Li, J; Huang, J; Xiong, Z; Zhang, Q; Chan, T; Ding, Y; Rau, C; Sung, K; Ren, S; Kulkarni, R; Hsiai, T; Xiao, X; Touma, M ...
Published in: J Clin Invest
October 1, 2020

In the mammalian heart, the left ventricle (LV) rapidly becomes more dominant in size and function over the right ventricle (RV) after birth. The molecular regulators responsible for this chamber-specific differential growth are largely unknown. We found that cardiomyocytes in the neonatal mouse RV had lower proliferation, more apoptosis, and a smaller average size compared with the LV. This chamber-specific growth pattern was associated with a selective activation of p38 mitogen-activated protein kinase (MAPK) activity in the RV and simultaneous inactivation in the LV. Cardiomyocyte-specific deletion of both the Mapk14 and Mapk11 genes in mice resulted in loss of p38 MAPK expression and activity in the neonatal heart. Inactivation of p38 activity led to a marked increase in cardiomyocyte proliferation and hypertrophy but diminished cardiomyocyte apoptosis, specifically in the RV. Consequently, the p38-inactivated hearts showed RV-specific enlargement postnatally, progressing to pulmonary hypertension and right heart failure at the adult stage. Chamber-specific p38 activity was associated with differential expression of dual-specific phosphatases (DUSPs) in neonatal hearts, including DUSP26. Unbiased transcriptome analysis revealed that IRE1α/XBP1-mediated gene regulation contributed to p38 MAPK-dependent regulation of neonatal cardiomyocyte proliferation and binucleation. These findings establish an obligatory role of DUSP/p38/IRE1α signaling in cardiomyocytes for chamber-specific growth in the postnatal heart.

Duke Scholars

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

October 1, 2020

Volume

130

Issue

10

Start / End Page

5287 / 5301

Location

United States

Related Subject Headings

  • Vascular Remodeling
  • Organ Specificity
  • Myocytes, Cardiac
  • Myocardium
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 14
  • Mice, Knockout
  • Mice
  • Male
  • Immunology
 

Citation

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Yokota, T., Li, J., Huang, J., Xiong, Z., Zhang, Q., Chan, T., … Wang, Y. (2020). p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart. J Clin Invest, 130(10), 5287–5301. https://doi.org/10.1172/JCI135859
Yokota, Tomohiro, Jin Li, Jijun Huang, Zhaojun Xiong, Qing Zhang, Tracey Chan, Yichen Ding, et al. “p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart.J Clin Invest 130, no. 10 (October 1, 2020): 5287–5301. https://doi.org/10.1172/JCI135859.
Yokota T, Li J, Huang J, Xiong Z, Zhang Q, Chan T, et al. p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart. J Clin Invest. 2020 Oct 1;130(10):5287–301.
Yokota, Tomohiro, et al. “p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart.J Clin Invest, vol. 130, no. 10, Oct. 2020, pp. 5287–301. Pubmed, doi:10.1172/JCI135859.
Yokota T, Li J, Huang J, Xiong Z, Zhang Q, Chan T, Ding Y, Rau C, Sung K, Ren S, Kulkarni R, Hsiai T, Xiao X, Touma M, Minamisawa S, Wang Y. p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart. J Clin Invest. 2020 Oct 1;130(10):5287–5301.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

October 1, 2020

Volume

130

Issue

10

Start / End Page

5287 / 5301

Location

United States

Related Subject Headings

  • Vascular Remodeling
  • Organ Specificity
  • Myocytes, Cardiac
  • Myocardium
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 14
  • Mice, Knockout
  • Mice
  • Male
  • Immunology