Abstract
Background
Previous studies manifested that abnormal proliferation, migration, apoptosis, and phenotypic conversion of vascular smooth muscle cells (VSMCs) are the main pathogenic basis of intracranial aneurysms (IAs).
Objective
The aim of this study was to explore a key gene associated with IA growth and rupture using bioinformatics analysis and validate it by exogenous overexpression into human brain VSMCs (HBVSMCs). Four IA-associated microarray datasets, GSE54083, GSE15629, GSE66238, and GSE13353, were obtained from Gene Expression Omnibus (GEO) and analyzed using GEO2R for differentially expressed genes (DEGs). HBVSMCs were infected with lentivirus containing RIO kinase 3 (RIOK3) to overexpress exogenous RIOK3, and then, CCK-8, EdU, cell scratch, Transwell, Western blotting, and ELISA were introduced to measure proliferation, migration, phenotypic conversion-related proteins, and proinflammatory cytokines in HBVSMCs. To simulate the abnormal hemodynamic environment in the late stages of IA formation, RIOK3-overexpressing HBVSMCs were cultured under wall shear stress (WSS)-loaded conditions and then subjected to apoptosis assessment.
Results
RIOK3 was defined as a key gene in the DEGs of IAs by bioinformatics analysis. RIOK3 overexpression could contribute to the abnormal proliferation, migration, secretion of proinflammatory factors, and the conversion of contractile phenotype to synthetic phenotype of HBVSMCs. Additionally, RIOK3 overexpression encouraged HBVSMC apoptosis after loading WSS in vitro to mimic advanced-IAs.
Conclusion
RIOK3 in pre-IAs (without WSS loading) facilitates phenotypic conversion, abnormal proliferation, invasion, and inflammatory cytokine secretion of HBVSMCs; whereas in the advanced-IAs, RIOK3 accelerated the abnormal apoptosis of HBVSMCs in the setting of loaded-WSS.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Baumas K et al (2012) Human RioK3 is a novel component of cytoplasmic pre-40S pre-ribosomal particles. RNA Biol 9:162–174
Cao G et al (2022) How vascular smooth muscle cell phenotype switching contributes to vascular disease. Cell Commun Signal 20:180
Cho DI et al (2023) ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. Exp Mol Med 55:426–442
Clough E, Barrett T (2016) The gene expression omnibus database. Methods Mol Biol 1418:93–110
D’Amato SA, Chang TR (2023) Advances in intracranial hemorrhage: subarachnoid hemorrhage and intracerebral hemorrhage. Crit Care Clin 39:71–85
Frösen J, Cebral J, Robertson AM, Aoki T (2019) Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms. Neurosurg Focus 47:E21
He C et al (2023) Autophagy and apoptosis in acute brain injuries: from mechanism to treatment. Antioxid Redox Signal 38:234–257
Hu Y, Fan Y, Zhang C, Wang C (2022a) Palmitic acid inhibits vascular smooth muscle cell switch to synthetic phenotype via upregulation of miR-22 expression. Aging (albany NY) 14:8046–8060
Hu Y et al (2022b) LncRNA ANRIL facilitates vascular smooth muscle cell proliferation and suppresses apoptosis via modulation of miR-7/FGF2 pathway in intracranial aneurysms. Neurocrit Care 36:106–115
Kancheva AK, Velthuis BK, Ruigrok YM (2022) Imaging markers of intracranial aneurysm development: a systematic review. J Neuroradiol 49:219–224
Kishizaki H et al (2022) A rare intracranial fusiform thrombosed aneurysm of the distal middle cerebral artery: a case report. Surg Neurol Int 13:57
Kosierkiewicz TA, Factor SM, Dickson DW (1994) Immunocytochemical studies of atherosclerotic lesions of cerebral berry aneurysms. J Neuropathol Exp Neurol 53:399–406
Li J et al (2022) A systematic pan-cancer analysis identifies RIOK3 as an immunological and prognostic biomarker. Am J Transl Res 14:3750–3768
Liu HJ et al (2019a) Intracranial mirror aneurysm: epidemiology, rupture risk, new imaging, controversies, and treatment strategies. World Neurosurg 127:165–175
Liu Z, Ajimu K, Yalikun N, Zheng Y, Xu F (2019b) Potential therapeutic strategies for intracranial aneurysms targeting aneurysm pathogenesis. Front Neurosci 13:1238
Pentimalli L et al (2004) Role of apoptosis in intracranial aneurysm rupture. J Neurosurg 101:1018–1025
Rahmanian A et al (2022) Evaluation of serum interleukin-1β (IL-1β) levels in patients with intracranial aneurysms compared to a control group. Turk Neurosurg 32:773–778
Ryu JY et al (2022) Wall shear stress on vascular smooth muscle cells exerts angiogenic effects on extracranial arteriovenous malformations. Arch Plast Surg 49:115–120
Shan J et al (2009) RIOK3 interacts with caspase-10 and negatively regulates the NF-kappaB signaling pathway. Mol Cell Biochem 332:113–120
Starke RM et al (2014a) Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res 5:338–346
Starke RM et al (2014b) Critical role of TNF-α in cerebral aneurysm formation and progression to rupture. J Neuroinflammation 11:77
Sulistyowati E et al (2022) Potential actions of baicalein for preventing vascular calcification of smooth muscle cells in vitro and in vivo. Int J Mol Sci 23:5673
Tang H et al (2021) Underlying mechanism of hemodynamics and intracranial aneurysm. Chin Neurosurg J 7:44
Tang HY et al (2022) Vascular smooth muscle cells phenotypic switching in cardiovascular diseases. Cells 11:4060
Tawk RG, Hasan TF, D’Souza CE, Peel JB, Freeman WD (2021) Diagnosis and treatment of unruptured intracranial aneurysms and aneurysmal subarachnoid hemorrhage. Mayo Clin Proc 96:1970–2000
Wang J, Varin T, Vieth M, Elkins JM (2019) Crystal structure of human RIOK2 bound to a specific inhibitor. Open Biol 9:190037
Wang Z et al (2023) Vascular smooth muscle cells in intracranial aneurysms. Microvasc Res 149:104554
Weinberg F et al (2017) The atypical kinase RIOK1 promotes tumor growth and invasive behavior. EBioMedicine 20:79–97
Xu M et al (2022) RIOK3 promotes pancreatic ductal adenocarcinoma cell invasion and metastasis by stabilizing FAK. Heliyon 8:e10116
Yan Y et al (2022) SDF-1α/CXCR4 pathway mediates hemodynamics-induced formation of intracranial aneurysm by modulating the phenotypic transformation of vascular smooth muscle cells. Transl Stroke Res 13:276–286
Zhang T et al (2018) The atypical protein kinase RIOK3 contributes to glioma cell proliferation/survival, migration/invasion and the AKT/mTOR signaling pathway. Cancer Lett 415:151–163
Zhang CY et al (2021a) Glutamine switches vascular smooth muscle cells to synthetic phenotype through inhibiting miR-143 expression and upregulating THY1 expression. Life Sci 277:119365
Zhang M et al (2021b) Associations between haemodynamics and wall enhancement of intracranial aneurysm. Stroke Vasc Neurol 6:467–475
Acknowledgement
None.
Funding
No funds, grants, or other support was received.
Author information
Authors and Affiliations
Contributions
In this work, JW and YT conceived the study and designed the experiments. YZ and BX contributed to the data collection, ZZ and JQ performed the data analysis and interpreted the results. JW wrote the manuscript. YT contributed to the critical revision of article. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
Author Jianzhu Wei declares that he has no conflict of interest. Author Yang Zhang declares that he has no conflict of interest. Author Bo Xie declares that he has no conflict of interest. Author Ziyi Zhu declares that he has no conflict of interest. Author Jingyu Qian declares that he has no conflict of interest. Author Yulin Tan declares that he has no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional afliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wei, J., Zhang, Y., Xie, B. et al. The atypical protein kinase RIOK3 contributes to the phenotypic modulation of vascular smooth muscle cells in intracranial aneurysms. Mol. Cell. Toxicol. (2024). https://doi.org/10.1007/s13273-023-00425-3
Accepted:
Published:
DOI: https://doi.org/10.1007/s13273-023-00425-3