Omentin-1 drives cardiomyocyte cell cycle arrest and metabolic maturation by interacting with BMP7
Omentin-1 drives cardiomyocyte cell cycle arrest and metabolic maturation by interacting with BMP7
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DOI：
10.1007/s00018-023-04829-1
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发表时间：
2023-07-01
影响因子：
8
通讯作者：
Nie，Yu
中科院分区：
文献类型：
--
作者：
Yang，Huijun;Song，Shen;Nie，Yu
哺乳动物心肌细胞（CM）在出生后的心脏发育过程中经历成熟，以满足增长的需求。在这里，我们发现omentin-1，一种脂肪因子，促进CM细胞周期停滞和代谢成熟。omentin-1的缺失导致小鼠成年期心脏增大和功能障碍，青少年期CM成熟延迟，包括细胞周期停滞延迟和脂肪酸氧化减少。通过RNA测序、分子对接分析和邻位连接分析，我们发现网膜蛋白-1通过直接与骨形态发生蛋白7（BMP 7）相互作用来调节CM成熟。Omentin-1阻止BMP 7与激活素II型受体B（ActRIIB）结合，随后减少针对DPP同源物1（SMAD 1）/Yes相关蛋白（雅普）和p38丝裂原活化蛋白激酶（p38 MAPK）的下游途径。此外，omentin-1对于人胚胎干细胞衍生的CM的成熟是必需的并且是足够的。总之，我们的研究结果表明，omentin-1是CM的促成熟因子，对出生后心脏发育和心脏功能维持至关重要。
Mammalian cardiomyocytes (CMs) undergo maturation during postnatal heart development to meet the increased demands of growth. Here, we found that omentin-1, an adipokine, facilitates CM cell cycle arrest and metabolic maturation. Deletion ofomentin-1causes mouse heart enlargement and dysfunction in adulthood and CM maturation retardation in juveniles, including delayed cell cycle arrest and reduced fatty acid oxidation. Through RNA sequencing, molecular docking analysis, and proximity ligation assays, we found that omentin-1 regulates CM maturation by interacting directly with bone morphogenetic protein 7 (BMP7). Omentin-1 prevents BMP7 from binding to activin type II receptor B (ActRIIB), subsequently decreasing the downstream pathways mothers against DPP homolog 1 (SMAD1)/Yes-associated protein (YAP) and p38 mitogen-activated protein kinase (p38 MAPK). In addition, omentin-1 is required and sufficient for the maturation of human embryonic stem cell-derived CMs. Together, our findings reveal that omentin-1 is a pro-maturation factor for CMs that is essential for postnatal heart development and cardiac function maintenance.