Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-04-04 DOI:10.1016/j.bcp.2025.116932

Heng Tang , Ke Ning , Boji Wu , Xuhong Wang , Jingyu He , Pingping Li , Lina Pan , Jiawen Zhang , Yi He , Shizhu Bian , Xingyu Ma , Jihang Zhang , Chuan Liu , Zhexue Qin , Houyuan Hu

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引用次数: 0

Abstract

Scutellarein (Sc), a natural flavonoid, holds potential for treating pulmonary arterial hypertension (PAH), yet its mechanisms remain unexplored. This study investigated Sc’s therapeutic effects and underlying pathways in PAH. In vivo experiments demonstrated that Sc significantly attenuated right ventricular hypertension, pulmonary arterial remodeling, αSMA expression, and vascular inflammation in PAH models. In vitro, Sc suppressed hypoxia-induced proliferation, migration, inflammation, and pyroptosis in human pulmonary artery smooth muscle cells (HPASMCs). Mechanistically, Sc activated the SIRT1/NAD⁺ axis to restore mitochondrial homeostasis: it upregulated SIRT1 expression and elevated NAD⁺ levels by promoting SIRT1-mediated deacetylation of nicotinamide nucleotide transhydrogenase (NNT), thereby enhancing NNT activity. Elevated NAD⁺ further activated SIRT1, forming a self-reinforcing SIRT1/NNT/NAD⁺ feedback loop that mitigated hypoxia-induced mitochondrial dysfunction. This study identifies Sc as a novel regulator of the SIRT1-dependent NNT deacetylation pathway, which stabilizes NAD⁺ homeostasis to counteract HPASMCs dysregulation in PAH. These findings highlight Sc’s potential as a therapeutic candidate for PAH, offering insights into targeting mitochondrial-metabolic pathways for vascular remodeling diseases.

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黄芩苷（Scutellarein，Sc）是一种天然类黄酮，具有治疗肺动脉高压（PAH）的潜力，但其作用机制仍有待探索。本研究调查了 Sc 在 PAH 中的治疗效果和潜在途径。体内实验表明，在 PAH 模型中，Sc 能显著减轻右室高血压、肺动脉重塑、αSMA 表达和血管炎症。在体外，Sc 可抑制缺氧诱导的人肺动脉平滑肌细胞（HPASMCs）的增殖、迁移、炎症和脓毒症。从机理上讲，Sc 激活了 SIRT1/NAD+ 轴以恢复线粒体平衡：它通过促进 SIRT1 介导的烟酰胺核苷酸转氢酶（NNT）去乙酰化，从而增强 NNT 活性，上调 SIRT1 的表达并提高 NAD+ 水平。升高的 NAD+ 进一步激活了 SIRT1，形成了一个自我强化的 SIRT1/NNT/NAD+ 反馈环，缓解了缺氧诱导的线粒体功能障碍。本研究发现 Sc 是 SIRT1 依赖性 NNT 去乙酰化途径的新型调节因子，它能稳定 NAD+ 的平衡，从而抵消 PAH 中 HPASMCs 的失调。这些发现凸显了 Sc 作为 PAH 候选疗法的潜力，为针对线粒体代谢途径治疗血管重塑疾病提供了启示。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.