PDF(Pubmed)
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.
摘要：
与不确定潜能（CHIP）的克隆造血相关的体细胞突变是中风的危险因素。DNMT3A的影响，CHIP中变异最多的基因,急性缺血性卒中(AIS)的临床功能结局尚不清楚.在一个由8524名缺血性卒中患者组成的特征明确的队列中，我们证明DNMT3A驱动的CHIP与这些患者的神经系统残疾显著相关.短暂性大脑中动脉闭塞（tMCAO）的中风小鼠模型，我们证明DNMT3A蛋白在大脑半影区的水平升高.DNMT3A抑制剂RG108的给药放大了血液中的中性粒细胞增殖，促进中性粒细胞浸润到大脑半影，和在tMCAO雄性小鼠中过度的促炎激活。在tMCAO雄性小鼠中,DNMT3A抑制也显著增加梗死体积并恶化神经行为功能。总之,DNMT3A体细胞突变与一些AIS患者的神经系统残疾恶化有关，可能通过增加中性粒细胞增殖和缺血脑区的浸润。这些研究结果表明，在受影响的脑组织中，促炎激活和组织损伤的可能机制。强调需要在这一领域进一步研究。
