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Administration of A. muciniphila ameliorates pulmonary arterial hypertension by targeting miR-208a-3p/NOVA1 axis

Acta Pharmacologica Sinica volume 44, pages 2201–2215 (2023)Cite this article

Abstract

Pulmonary arterial hypertension (PH) is a chronic disease induced by a progressive increase in pulmonary vascular resistance and failure of the right heart function. A number of studies show that the development of PH is closely related to the gut microbiota, and lung-gut axis might be a potential therapeutic target in the PH treatment. A. muciniphila has been reported to play a critical role in treating cardiovascular disorders. In this study we evaluated the therapeutic effects of A. muciniphila against hypoxia-induced PH and the underlying mechanisms. Mice were pretreated with A. muciniphila suspension (2 × 108 CFU in 200 μL sterile anaerobic PBS, i.g.) every day for 3 weeks, and then exposed to hypoxia (9% O2) for another 4 weeks to induce PH. We showed that A. muciniphila pretreatment significantly facilitated the restoration of the hemodynamics and structure of the cardiopulmonary system, reversed the pathological progression of hypoxia-induced PH. Moreover, A. muciniphila pretreatment significantly modulated the gut microbiota in hypoxia-induced PH mice. miRNA sequencing analysis reveals that miR-208a-3p, a commensal gut bacteria-regulated miRNA, was markedly downregulated in lung tissues exposed to hypoxia, which was restored by A. muciniphila pretreatment. We showed that transfection with miR-208a-3p mimic reversed hypoxia-induced abnormal proliferation of human pulmonary artery smooth muscle cells (hPASMCs) via regulating the cell cycle, whereas knockdown of miR-208a-3p abolished the beneficial effects of A. muciniphila pretreatment in hypoxia-induced PH mice. We demonstrated that miR-208a-3p bound to the 3′-untranslated region of NOVA1 mRNA; the expression of NOVA1 was upregulated in lung tissues exposed to hypoxia, which was reversed by A. muciniphila pretreatment. Furthermore, silencing of NOVA1 reversed hypoxia-induced abnormal proliferation of hPASMCs through cell cycle modulation. Our results demonstrate that A. muciniphila could modulate PH through the miR-208a-3p/NOVA1 axis, providing a new theoretical basis for PH treatment.

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Fig. 1: Gavage of A. muciniphila improved hypoxia-induced PH.
Fig. 2: A. muciniphila altered gut microbiota in hypoxia-induced PH mice.
Fig. 3: A. muciniphila could regulate the expression of miR-208a-3p in hypoxia condition.
Fig. 4: MiR-208a-3p mimic inhibited the proliferation of hPASMCs under hypoxia condition.
Fig. 5: Knockdown of miR-208a-3p reversed the effects of A. muciniphila on hypoxia-induced PH.
Fig. 6: A. muciniphila decreased the expression of NOVA1 by regulating miR-208a-3p.
Fig. 7: NOVA1 silencing regulated proliferation and cell cycle of hPASMCs.
Fig. 8: Schematic diagram illustrating the proposed mechanisms of the effects of A. muciniphila on PH.

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Acknowledgements

The research was supported by the National Key Research and Development Program of China (2021YFA1301100, 2021YFA1301101, 2022YFA1303801), the Research Project of Ji-nan Microecological Biomedicine Shandong Laboratory (JNL-2022001A) and the Fundamental Research Funds for the Central Universities (No. 2022ZFJH003).

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  1. These authors contributed equally: Zheng-yi Bao, Hui-min Li

Authors and Affiliations

  1. State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China

    Zheng-yi Bao, Shuo-bo Zhang, Yi-qiu Fei, Ming-fei Yao & Lan-juan Li

  2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201100, China

    Hui-min Li

  3. Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100010, China

    Ming-fei Yao & Lan-juan Li

  4. Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China

    Lan-juan Li

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LJL and MFY designed the research and wrote the paper. ZYB and HML performed major experiments and analyzed the data. SBZ and YQF performed animal experiments. All the authors approved the final paper.

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Correspondence to Ming-fei Yao or Lan-juan Li.

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Bao, Zy., Li, Hm., Zhang, Sb. et al. Administration of A. muciniphila ameliorates pulmonary arterial hypertension by targeting miR-208a-3p/NOVA1 axis. Acta Pharmacol Sin 44, 2201–2215 (2023). https://doi.org/10.1038/s41401-023-01126-2

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