p38 MAPK reins in right ventricular growth
Tongbin Wu, Ju Chen
Tongbin Wu, Ju Chen
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Commentary

p38 MAPK reins in right ventricular growth

Abstract

The right ventricle (RV) is involved in systemic circulation in the fetal mammalian heart but quickly transitions to being solely responsible for pulmonary circulation after birth when the left ventricle (LV) becomes the systemic ventricle. To handle the increased workload, LV growth greatly outpaces that of the RV during postnatal stages. However, the molecular basis for this differential growth pattern between the 2 chambers is largely unknown. In this issue of the JCI, Yokota et al. reveal that the p38 mitogen-activated protein kinase (MAPK)/IRE1α/XBP1 axis specifically controls postnatal RV growth by suppressing cell cycle regulatory genes.

Authors

Tongbin Wu, Ju Chen

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Figure 1

Model of DUSP26/p38 MAPK/IRE1α/XBP1 pathway in controlling cardiomyocyte (CM) proliferation in ventricles.

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Model of DUSP26/p38 MAPK/IRE1α/XBP1 pathway in controlling cardiomyocyte...
(A) In the WT neonatal heart, low DUSP26 levels in the RV are insufficient to dephosphorylate p38 MAPK, which in turn represses the expression of IRE1α and shuts down the IRE1α/XBP1 pathway, leading to lower CM proliferation in the RV. In contrast, LV-enriched DUSP26 dephosphorylates p38 MAPK, thus relieving p38 MAPK’s inhibitory effect on the expression of IRE1α, which splices Xbp1 mRNA to generate the sXbp1 isoform. sXBP1 then translocates to the nucleus and drives the expression of cell cycle–related genes, promoting CM proliferation. (B) In the p38-cdKO heart, the expression of IRE1α in the RV is no longer repressed by p38 MAPK, resulting in ectopic activation of the IRE1α/XBP1 pathway, which ultimately leads to excessive RV growth and dysfunction. In contrast, the p38-cdKO LV is unaffected because p38 MAPK activity is already very low in the WT LV.