Inhibition of DYRK1A attenuates vascular remodeling in pulmonary arterial hypertension via suppressing STAT3/Pim-1/NFAT pathway.

IF 1.5 4区 医学 Q3 PERIPHERAL VASCULAR DISEASE Clinical and Experimental Hypertension Pub Date : 2024-12-31 Epub Date: 2023-12-26 DOI:10.1080/10641963.2023.2297642
Cong Lan, Guangyao Fang, Chenming Qiu, Xiuchuan Li, Fengyuan Yang, Yongjian Yang
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Abstract

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.

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抑制 DYRK1A 可通过抑制 STAT3/Pim-1/NFAT 通路减轻肺动脉高压的血管重塑。
肺动脉高压(PAH)的特征是肺动脉平滑肌细胞(PASMC)过度增殖和存活导致的进行性血管重塑。双特异性酪氨酸调控激酶 1A(DYRK1A)是一种多效激酶,参与调控多种生物功能,包括细胞增殖和存活。然而,DYRK1A 在 PAH 发病机制中的作用和潜在机制仍不清楚。我们发现,在体内和体外,DYRK1A 在 PASMCs 对缺氧的反应中上调。用荷马碱抑制 DYRK1A 能显著减轻缺氧诱导的肺动脉高压和肺动脉重塑。从机理上讲,我们发现DYRK1A通过激活STAT3/Pim-1/NFAT通路增强了PASMCs的增殖和存活,从而促进了肺动脉重塑,因为通过携带组成型活性STAT3(STAT3C)的腺相关病毒血清型2(AAV2)进行STAT3功能增益几乎取消了哈米宁对PAH的保护作用。总之,我们的研究结果揭示了 DYRK1A 在肺动脉重塑中的重要作用,并建议将其作为治疗 PAH 的一个具有转化潜力的药物靶点。
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来源期刊
CiteScore
3.90
自引率
0.80%
发文量
66
审稿时长
6-12 weeks
期刊介绍: Clinical and Experimental Hypertension is a reputable journal that has converted to a full Open Access format starting from Volume 45 in 2023. While previous volumes are still accessible through a Pay to Read model, the journal now provides free and open access to its content. It serves as an international platform for the exchange of up-to-date scientific and clinical information concerning both human and animal hypertension. The journal publishes a wide range of articles, including full research papers, solicited and unsolicited reviews, and commentaries. Through these publications, the journal aims to enhance current understanding and support the timely detection, management, control, and prevention of hypertension-related conditions. One notable aspect of Clinical and Experimental Hypertension is its coverage of special issues that focus on the proceedings of symposia dedicated to hypertension research. This feature allows researchers and clinicians to delve deeper into the latest advancements in this field. The journal is abstracted and indexed in several renowned databases, including Pharmacoeconomics and Outcomes News (Online), Reactions Weekly (Online), CABI, EBSCOhost, Elsevier BV, International Atomic Energy Agency, and the National Library of Medicine, among others. These affiliations ensure that the journal's content receives broad visibility and facilitates its discoverability by professionals and researchers in related disciplines.
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