Atherosclerosis plus · 2026
Role and mechanism of G9A-BMP2 in calcification-induced formation of unstable plaque.
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Yang Wenjuan, Ma Zheng, Cui Ying, Jia Shaobin
Аннотация
BACKGROUND: G9A, a histone methyltransferase that facilitates H3K9 dimethylation, has been implicated in the epigenetic regulation of vascular processes. This study encapsulates its involvement in the calcification and stability of atherosclerotic plaques, further investigating its interaction with bone morphogenetic protein 2 (BMP2), a pivotal factor in vascular calcification, unveiling that G9A fosters plaque calcification and instability via the BMP2 signaling pathway.
METHODS: The progression of unstable plaques, histone methylation status, and vascular calcification incidence were monitored in the carotid plaques of ApoE-/- mice subjected to a high-fat diet over 30 weeks. Additionally, these parameters were scrutinized in pathological specimens from patients who underwent carotid plaque excision. In vitro, rat thoracic aortic smooth muscle A7R5 cells were cultured, with the G9A gene being manipulated through techniques of gene knockdown and overexpression.
RESULTS: In ApoE-/-mice and human carotid arteries, calcification exacerbated plaque instability in the context of a high-fat diet. This phenomenon was accompanied by elevated levels of G9A and dimethylation of histone H3 at lysine 9, alongside G9A expression in vitro. The absence of G9A in vitro impeded the calcification process of vascular smooth muscle cells (VSMCs), whereas G9A overexpression prompted a shift in the phenotypic attributes of smooth muscle cells.
CONCLUSIONS: Our findings indicate that G9A amplifies vascular calcification through the activation of Bmp2 signaling, a fundamental mediator of vascular calcification. The relationship between vascular calcification and the emergence of unstable plaques may be intricately associated with histone methylation.
METHODS: The progression of unstable plaques, histone methylation status, and vascular calcification incidence were monitored in the carotid plaques of ApoE-/- mice subjected to a high-fat diet over 30 weeks. Additionally, these parameters were scrutinized in pathological specimens from patients who underwent carotid plaque excision. In vitro, rat thoracic aortic smooth muscle A7R5 cells were cultured, with the G9A gene being manipulated through techniques of gene knockdown and overexpression.
RESULTS: In ApoE-/-mice and human carotid arteries, calcification exacerbated plaque instability in the context of a high-fat diet. This phenomenon was accompanied by elevated levels of G9A and dimethylation of histone H3 at lysine 9, alongside G9A expression in vitro. The absence of G9A in vitro impeded the calcification process of vascular smooth muscle cells (VSMCs), whereas G9A overexpression prompted a shift in the phenotypic attributes of smooth muscle cells.
CONCLUSIONS: Our findings indicate that G9A amplifies vascular calcification through the activation of Bmp2 signaling, a fundamental mediator of vascular calcification. The relationship between vascular calcification and the emergence of unstable plaques may be intricately associated with histone methylation.