Autor: |
Tian‐Jie Lyu, Xin Qiu, Yubo Wang, Ling Zhang, Yalun Dai, Xuechun Wang, Shunying Zhao, Meilin Xiang, Lu Cui, Si Cheng, Yang Liu, Hongqiu Gu, Yong Jiang, Xia Meng, Yilong Wang, Xingquan Zhao, Xianwei Wang, Qian Li, Meng Wang, Yingyu Jiang, Zhe Xu, Xinying Huang, Hao Li, Yongjun Wang, Zixiao Li |
Jazyk: |
angličtina |
Rok vydání: |
2024 |
Předmět: |
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Zdroj: |
MedComm, Vol 5, Iss 7, Pp n/a-n/a (2024) |
Druh dokumentu: |
article |
ISSN: |
2688-2663 |
DOI: |
10.1002/mco2.652 |
Popis: |
Abstract Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well‐characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A‐driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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