دورية أكاديمية
KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway.
العنوان: | KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway. |
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المؤلفون: | Xu H; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Huo R; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Li H; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Jiao Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Weng J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Wang J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Yan Z; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Zhang J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Zhao S; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., He Q; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Sun Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Wang S; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Cao Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China caoyong@bjtth.org.; China National Clinical Research Center for Neurological Diseases, Beijing, China.; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. |
المصدر: | Stroke and vascular neurology [Stroke Vasc Neurol] 2023 Jun; Vol. 8 (3), pp. 197-206. Date of Electronic Publication: 2022 Nov 23. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: BMJ Country of Publication: England NLM ID: 101689996 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2059-8696 (Electronic) Linking ISSN: 20598688 NLM ISO Abbreviation: Stroke Vasc Neurol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : BMJ, [2016]- |
مواضيع طبية MeSH: | Transforming Growth Factor beta*/metabolism , Intracranial Arteriovenous Malformations*/genetics, Humans ; Mice ; Animals ; Proto-Oncogene Proteins p21(ras)/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Human Umbilical Vein Endothelial Cells/metabolism ; Mutation ; Brain/metabolism ; Smad4 Protein/genetics ; Smad4 Protein/metabolism |
مستخلص: | Objective: Somatic KRAS mutations have been identified in the majority of brain arteriovenous malformations (bAVMs), and subsequent in vivo experiments have confirmed that KRAS mutation in endothelial cells (ECs) causes AVMs in mouse and zebrafish models. Our previous study demonstrated that the KRAS G12D mutant independently induced the endothelial-mesenchymal transition (EndMT), which was reversed by treatment with the lipid-lowering drug lovastatin. However, the underlying mechanisms of action were unclear. Methods: We used human umbilical vein ECs (HUVECs) overexpressing the KRAS G12D mutant for Western blotting, quantitative real-time PCR, and immunofluorescence and wound healing assays to evaluate the EndMT and determine the activation of downstream pathways. Knockdown of SMAD4 by RNA interference was performed to explore the role of SMAD4 in regulating the EndMT. BAVM ECs expressing the KRAS G12D mutant were obtained to verify the SMAD4 function. Finally, we performed a coimmunoprecipitation assay to probe the mechanism by which lovastatin affects SMAD4. Results: HUVECs infected with KRAS G12D adenovirus underwent the EndMT. Transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signalling pathways were activated in the KRAS G12D -mutant HUVECs and ECs in bAVM tissue. Knocking down SMAD4 expression in both KRAS G12D -mutant HUVECs and ECs in bAVM tissues inhibited the EndMT. Lovastatin attenuated the EndMT by downregulating p-SMAD2/3, p-SMAD1/5 and acetylated SMAD4 expression in KRAS G12D -mutant HUVECs. Conclusions: Our findings suggest that the KRAS G12D mutant induces the EndMT by activating the ERK-TGF-β/BMP-SMAD4 signalling pathway and that lovastatin inhibits the EndMT by suppressing TGF-β/BMP pathway activation and SMAD4 acetylation. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) |
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فهرسة مساهمة: | Keywords: Arteriovenous Malformations |
المشرفين على المادة: | 0 (Transforming Growth Factor beta) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) 0 (SMAD4 protein, human) 0 (Smad4 Protein) 0 (KRAS protein, human) |
تواريخ الأحداث: | Date Created: 20221123 Date Completed: 20230626 Latest Revision: 20230821 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC10359780 |
DOI: | 10.1136/svn-2022-001700 |
PMID: | 36418055 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2059-8696 |
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DOI: | 10.1136/svn-2022-001700 |