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Omentin-1 drives cardiomyocyte cell cycle arrest and metabolic maturation by interacting with BMP7

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Abstract

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 of omentin-1 causes 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.

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Data availability

The sequencing datasets involved in this work have been deposited in the NCBI database under project accession number PRJNA681365.

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Acknowledgements

We are grateful to Dr. Hui Xie (Movement System Injury and Repair Research Center, Xiangya Hospital, Changsha, China) for the generation and provision of omentin-1−/− mice. We acknowledge the experimental research center of the Chinese Academy of Medical Sciences for the use of the IonOptix Systems. We also acknowledge the service of the public laboratory platform at the State Key Laboratory of Cardiovascular Disease for their assistance in flow cytometry (Shuo Gao), tissue sectioning (Jian Meng and Zhenyu Xu), and CardioExcyte 96 function analysis experiments (Kejia Zhong). We are grateful Weijing Liu, Zheng Qiao, Chiyin Wang, Wenlong Zhang, Shijie Sun, Haorui Liu, Wenzheng Chen, Zehao Yao, Yunxiaoxiao Wu, Hao Wang, Yuan Zhang, Yuan Liu, and Shanshan Xu for the proof, and polishing of the manuscript.

Funding

This work was supported by the National Key Research and Development Project of China (grant number 2019YFA0801500), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CAMS-I2M, 2021-I2M-1–072; 2021-I2M-C&T-A-011), the National Natural Science Foundation of China (grant number 81873509, 81970243, 81822004, 81670267, 81873479, and 31801068), and the Innovation-driven Project of Central South University (No. 2020CX017).

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Author notes

  1. Huijun Yang and Shen Song have contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China

    Huijun Yang, Quan Sun, Xueting Qiu, Yongping Bai & Guogang Zhang

  2. State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Street, Beilishi Road, Xicheng District, Beijing, 100037, People’s Republic of China

    Huijun Yang, Shen Song, Yandong Li, Jie Feng, Ziwei Chen, Xue Bai, Xinchang Liu, Hong Lian, Lihui Liu & Yu Nie

  3. Department of Cardiovascular Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China

    Huijun Yang

  4. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Jiacheng Li

  5. Department of Geriatric Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 87 Street, Xiangya Road, Kaifu District, Changsha, 410008, People’s Republic of China

    Quan Sun, Xueting Qiu, Yongping Bai & Guogang Zhang

  6. Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, 518057, China

    Yu Nie

  7. National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Fuwai Central-China Hospital, Central China Branch of National Center for Cardiovascular Diseases, Zhengzhou, 450046, China

    Yu Nie

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  1. Huijun Yang
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  2. Shen Song
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Contributions

HY conceived the project, performed experiments, analyzed data, and wrote the manuscript. SS analyzed RNA-seq data and edited the manuscript. JL and JF performed primary CM isolation experiments. YL performed apical resection models. ZC performed echocardiography. QS and XQ performed animal experiments. XB and XL rewrote and revised the manuscript. HL and LL analyzed data. YB and GZ participated in project design. YN designed and planned the project and wrote the manuscript.

Corresponding authors

Correspondence to Yongping Bai, Guogang Zhang or Yu Nie.

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The authors declare no competing interests.

Ethical approval

The animal experiments were conducted in accordance with the Guide for the Use and Care of Laboratory Animals. All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC), Fuwai Hospital, Chinese Academy of Medical Sciences.

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Yang, H., Song, S., Li, J. et al. Omentin-1 drives cardiomyocyte cell cycle arrest and metabolic maturation by interacting with BMP7. Cell. Mol. Life Sci. 80, 186 (2023). https://doi.org/10.1007/s00018-023-04829-1

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