Journal Article

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

Huang, Jijun, Yokota, Tomohiro, Sung, Kevin, Xiao, Xinshu, Rau, Christoph, Hsiai, Tzung, Ren, Shuxun, Chan, Tracey, Wang, Yibin, Xiong, Zhaojun, Ding, Yichen, Kulkarni, Rajan, Minamisawa, Susumu, Li, Jin, Zhang, Qing, Touma, Marlin

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Animals, Newborn / Apoptosis / Biomedical research / Cardiomyocytes / Cell cycle / Cell Proliferation / Cell Size / Comparative analysis / Congestive heart failure / Enzyme Activation / Female / Gene expression / Gene Expression Profiling / Gene regulation / Growth / Growth patterns / Heart / Heart - growth & development / Heart failure / Heart Ventricles - cytology / Heart Ventricles - enzymology / Heart Ventricles - growth & development / Hypertrophy / Kinases / Male / MAP kinase / Mice / Mice, Knockout / Mitogen-Activated Protein Kinase 14 - deficiency / Mitogen-Activated Protein Kinase 14 - genetics / Mitogen-Activated Protein Kinase 14 - metabolism / Mitogen-Activated Protein Kinases - deficiency / Mitogen-Activated Protein Kinases - genetics / Mitogen-Activated Protein Kinases - metabolism / Mitogens / Myocardium - cytology / Myocardium - enzymology / Myocytes, Cardiac - cytology / Myocytes, Cardiac - enzymology / Neonates / Newborn infants / Organ Specificity / Phosphatase / Phosphatases / Protein kinase / Protein kinases / Proteins / Pulmonary hypertension / Vascular Remodeling - genetics / Vascular Remodeling - physiology / Ventricle