Novel carbazole attenuates vascular remodeling through STAT3/CIAPIN1 signaling in vascular smooth muscle cells

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B Pub Date : 2025-03-01 DOI:10.1016/j.apsb.2024.12.035

Joo-Hui Han , Jong-Beom Heo , Hyung-Won Lee , Min-Ho Park , Jangmi Choi , Eun Joo Yun , Seongpyo Lee , Gyu Yong Song , Chang-Seon Myung

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Abstract

This study investigated the molecular mechanism of phenotypic switching of vascular smooth muscle cells (VSMCs), which play a crucial role in vascular remodeling using 9H-Carbazol-3-yl 4-aminobenzoate (CAB). CAB significantly attenuated platelet-derived growth factor (PDGF)-induced VSMC proliferation and migration. CAB suppressed PDGF-induced STAT3 activation by directly binding to the SH2 domain of STAT3. Downregulation of STAT3 phosphorylation by CAB attenuated CIAPIN1/JAK2/STAT3 axis through a decrease in CIAPIN1 transcription. Furthermore, abrogated CIAPIN1 decreased KLF4-mediated VSMC dedifferentiation and increased CDKN1B-induced cell cycle arrest and MMP9 suppression. CAB inhibited intimal hyperplasia in injury-induced neointima animal models by inhibition of the CIAPIN1/JAK2/STAT3 axis. However, CIAPIN1 overexpression attenuated CAB-mediated suppression of VSMC proliferation, migration, phenotypic switching, and intimal hyperplasia. Our study clarified the molecular mechanism underlying STAT3 inhibition of VSMC phenotypic switching and vascular remodeling and identified novel active CAB. These findings demonstrated that STAT3 can be a major regulator to control CIAPIN1/JAK2/STAT3 axis that may be a therapeutic target for treating vascular proliferative diseases.

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新型咔唑通过血管平滑肌细胞中STAT3/CIAPIN1信号通路减弱血管重构

本研究探讨了9H-Carbazol-3-yl - 4-氨基苯甲酸酯（CAB）对血管平滑肌细胞（VSMCs）表型转换的分子机制，VSMCs在血管重塑中起着至关重要的作用。CAB显著减弱血小板衍生生长因子（PDGF）诱导的VSMC增殖和迁移。CAB通过直接结合STAT3的SH2结构域抑制pdgf诱导的STAT3激活。CAB下调STAT3磷酸化通过减少CIAPIN1转录，减弱了CIAPIN1/JAK2/STAT3轴。此外，取消CIAPIN1减少了klf4介导的VSMC去分化，增加了cdkn1b诱导的细胞周期阻滞和MMP9抑制。CAB通过抑制CIAPIN1/JAK2/STAT3轴抑制损伤性新生内膜动物模型的内膜增生。然而，CIAPIN1过表达减弱了cab介导的VSMC增殖、迁移、表型转换和内膜增生的抑制。我们的研究阐明了STAT3抑制VSMC表型转换和血管重塑的分子机制，并鉴定了新的活性CAB。这些发现表明STAT3可能是控制CIAPIN1/JAK2/STAT3轴的主要调节因子，可能是治疗血管增生性疾病的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics

CiteScore

22.40

自引率

5.50%

发文量

1051

审稿时长

19 weeks

期刊介绍： The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.