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

Zheng-yi Bao1, Hui-min Li2, Shuo-bo Zhang1, Yi-qiu Fei1, Ming-fei Yao1,3, Lan-juan Li1,3,4
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
2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201100, China
3 Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing 100010, China
4 Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
Correspondence to: Ming-fei Yao:, Lan-juan Li:,
DOI: 10.1038/s41401-023-01126-2
Received: 22 December 2022
Accepted: 8 June 2023
Advance online: 11 July 2023


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.

Keywords: A. muciniphila; pulmonary arterial hypertension; MicroRNA; lung-gut axis; proliferation

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