Cardiovascular Research Laboratories, Department of Anesthesiology, Department of Physiology, and Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Department of Cardiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
J Clin Invest. 2020 Oct 1;130(10):5287-5301. doi: 10.1172/JCI135859.
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.
在哺乳动物的心脏中,左心室(LV)在出生后迅速变得比右心室(RV)在大小和功能上更为突出。负责这种腔室特异性差异生长的分子调节剂在很大程度上是未知的。我们发现,与 LV 相比,新生小鼠 RV 中的心肌细胞增殖能力较低,凋亡较多,平均体积较小。这种腔室特异性生长模式与 RV 中 p38 丝裂原活化蛋白激酶(MAPK)活性的选择性激活以及 LV 中同时失活有关。在小鼠中,心肌细胞特异性缺失 Mapk14 和 Mapk11 基因导致新生心脏中 p38 MAPK 的表达和活性丧失。p38 活性的失活导致心肌细胞增殖和肥大的显著增加,但 RV 中的心肌细胞凋亡减少。因此,p38 失活的心脏在出生后表现出 RV 特异性增大,在成年期进展为肺动脉高压和右心衰竭。腔室特异性 p38 活性与新生儿心脏中双特异性磷酸酶(DUSPs)的差异表达有关,包括 DUSP26。无偏转录组分析显示,IRE1α/XBP1 介导的基因调节有助于 p38 MAPK 依赖的新生儿心肌细胞增殖和双核化调节。这些发现确立了 DUSP/p38/IRE1α 信号在心肌细胞中的必需作用,以实现出生后心脏的腔室特异性生长。