Unraveling the Mfn2-Warburg effect nexus: a therapeutic strategy to combat pulmonary arterial hypertension arising from catch-up growth after IUGR.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-09-02 DOI:10.1186/s12931-024-02957-1
Lingling Yan, Xiaofei Luo, Chengcheng Hang, YuWang, Ziming Zhang, Shanshan Xu, Lizhong Du
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Abstract

Background: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.

Methods and results: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.

Conclusions: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.

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揭示 Mfn2-Warburg 效应关系:应对 IUGR 后追赶生长引起的肺动脉高压的治疗策略。
背景:宫内环境和出生后早期环境之间的相互作用与成年后心血管疾病(包括肺动脉高压(PAH))风险的增加有关。虽然新出现的证据强调了线粒体病理学在 PAH 中的关键作用,但驱动胎儿源性 PAH 的具体机制仍然难以捉摸:为了阐明线粒体动力学在胎儿源性 PAH 发病机制中的作用,我们建立了宫内生长受限(IUGR)后出生后追赶生长的大鼠模型,诱发肺动脉高压(PAH)。对大鼠肺动脉样本进行的 RNA-seq 分析发现,线粒体代谢基因和通路失调与 RC 组(IUGR 后的产后追赶生长)肺动脉压力升高和肺动脉重塑有关。使用 RC 组的肺动脉平滑肌细胞(PASMCs)进行的体外实验表明,RC 组的肺动脉平滑肌细胞增殖、迁移和线粒体功能受损。值得注意的是,在 RC 组中观察到线粒体外膜蛋白 Mitofusion 2(Mfn2)的表达减少。重建 Mfn2 可增强线粒体融合,改善 RC 组 PASMC 的线粒体功能,有效逆转沃伯格效应。重要的是,Mfn2重组减轻了RC组大鼠的PAH表型:结论:线粒体动力学失衡(以 Mfn2 表达减少为特征)在 IUGR 出生后追赶生长过程中胎儿源 PAH 的发展中起着关键作用。Mfn2是治疗IUGR-追赶生长诱发的PAH的一种有前景的治疗策略。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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