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.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201100, China.
Acta Pharmacol Sin. 2023 Nov;44(11):2201-2215. doi: 10.1038/s41401-023-01126-2. Epub 2023 Jul 11.
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 × 10 CFU in 200 μL sterile anaerobic PBS, i.g.) every day for 3 weeks, and then exposed to hypoxia (9% O) 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.
肺动脉高压（PH）是一种由肺血管阻力进行性增加和右心功能衰竭引起的慢性疾病。许多研究表明，PH 的发展与肠道微生物群密切相关，肺-肠轴可能是 PH 治疗的潜在治疗靶点。黏蛋白阿克曼菌已被报道在治疗心血管疾病方面发挥关键作用。在这项研究中，我们评估了黏蛋白阿克曼菌对缺氧诱导的 PH 的治疗效果及其潜在机制。小鼠每天用黏蛋白阿克曼菌悬浮液（2×10 CFU 在 200μL 无菌厌氧 PBS 中，ig）预处理 3 周，然后暴露于低氧（9% O）4 周以诱导 PH。我们表明，黏蛋白阿克曼菌预处理显著促进了心肺系统的血液动力学和结构的恢复，逆转了缺氧诱导的 PH 的病理进展。此外，黏蛋白阿克曼菌预处理显著调节了缺氧诱导的 PH 小鼠的肠道微生物群。miRNA 测序分析表明，在暴露于低氧的肺组织中，一种共生肠道细菌调节的 miRNA miR-208a-3p 显著下调，而黏蛋白阿克曼菌预处理则使其恢复。我们表明，转染 miR-208a-3p 模拟物通过调节细胞周期逆转了缺氧诱导的人肺动脉平滑肌细胞（hPASMCs）的异常增殖，而 miR-208a-3p 的敲低则消除了黏蛋白阿克曼菌预处理在缺氧诱导的 PH 小鼠中的有益作用。我们证明了 miR-208a-3p 结合到 NOVAl mRNA 的 3'-非翻译区；NOVA1 的表达在暴露于低氧的肺组织中上调，而黏蛋白阿克曼菌预处理则使其逆转。此外，NOVA1 的沉默通过细胞周期调节逆转了缺氧诱导的 hPASMCs 的异常增殖。我们的结果表明，黏蛋白阿克曼菌可以通过 miR-208a-3p/NOVA1 轴调节 PH，为 PH 治疗提供了新的理论基础。
