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MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling

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Abstract

Abnormal pulmonary arterial smooth muscle cells (PASMCs) proliferation is an important pathological process in hypoxic pulmonary arterial hypertension. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation–apoptosis balance. However, the molecular mechanism is still unknown. We used hypoxic animal models, cell biology, and molecular biology to determine the effect of mitofusin 1 (Mfn1) on hypoxia-mediated PASMCs mitochondrial homeostasis. We found that Mfn1 expression was increased in hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and smooth muscle cell proliferation as well as hypoxia-stimulated cell-cycle transition from the G0/G1 phase to S phase. Subsequently, we studied the role of microRNAs in mitochondrial function associated with PASMC proliferation under hypoxic conditions. The promotive effect of Mfn1 on pulmonary vascular remodeling was alleviated in the presence of miR-125a agomir, and miR-125a antagomir mimicked the hypoxic damage effects to mitochondrial homeostasis. Moreover, in vivo and in vitro treatment with miR-125a agomir protected the pulmonary vessels from mitochondrial dysfunction and abnormal remodeling. In the present study, we determined that mitochondrial homeostasis, particularly Mfn1, played an important role in PASMCs proliferation. MiR-125a, an important underlying factor, which inhibited Mfn1 expression and decreased PASMCs disordered growth during hypoxia. These results provide a theoretical basis for the prevention and treatment of pulmonary vascular remodeling.

Key messages

  • Hypoxia leads to upregulation of mitofusin 1 (Mfn1) both in vivo and in vitro.

  • Mfn1 is involved in hypoxia-induced PASMCs proliferation.

  • Mfn1-mediated mitochondrial homeostasis is regulated by miR-125a.

  • MiR-125a plays a role in PASMCs oxidative phosphorylation and glycolysis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [31471095, 81270113, and 81400353]; the Key Research Plan of National Natural Science Foundation of China [91339107]; the Natural Science Foundation of Heilongjiang Province [QC2014C096]; the Wu Liande Youth Science Foundation [WLD-QN1410]; the Postdoctoral Foundation of Heilongjiang Province [LBH-Z14133]; and the Postdoctoral Foundation of China [2015m571438].

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Author notes

  1. Cui Ma and Chen Zhang contributed equally to this work.

Authors and Affiliations

  1. College of Medical Laboratory Science and Technology, Harbin Medical University, Daqing, China

    Cui Ma, Yingli Chen & Yumei Liu

  2. Central Laboratory, Harbin Medical University, Daqing, China

    Chen Zhang, Mingfei Ma, Lixin Zhang, Linlin Zhang, Fengying Zhang, Tingting Shen, Hongmin Yao, Shasha Song & Daling Zhu

  3. College of Basic Medicine, Harbin Medical University, Daqing, China

    Fangyuan Cao

  4. College of Pharmacy, Harbin Medical University, Xinyang Road, Daqing, Heilongjiang, 163319, People’s Republic of China

    Minghui Li, Guangtian Wang, Zhenwei Pan & Daling Zhu

  5. Key Laboratory of Pulmonary Circulatory System Diseases of Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang, China

    Daling Zhu

  6. State Province Key Laboratories of Biomedicine—Pharmaceutics of China, Daqing, China

    Daling Zhu

  7. Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Daqing, China

    Daling Zhu

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  1. Cui Ma
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Correspondence to Daling Zhu.

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All animal care and experimental procedures were performed in accordance with relevant guidelines and regulations and approved by the Institutional Animal Care and Use Committee (IACUC) of Harbin Medical University.

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The authors declare that they have no conflict of interests.

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Ma, C., Zhang, C., Ma, M. et al. MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling. J Mol Med 95, 977–993 (2017). https://doi.org/10.1007/s00109-017-1541-5

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