Yan Zi, Zhao Wenhui, Zhao Naixin, Liu Yufeng, Yang Bowen, Wang Li, Liu Jingyi, Wang Deping, Wang Jin, Jiao Xiangying, Cao Jimin, Li Jianguo
Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
MOE Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan 030001, China.
Acta Biochim Biophys Sin (Shanghai). 2024 Dec 10. doi: 10.3724/abbs.2024175.
Myocardial hypertrophy (MH) is an important factor contributing to severe cardiovascular disease. Previous studies have demonstrated that specific deletion of the protein arginine methyltransferase 1 (PRMT1) leads to MH, but the exact mechanism remains unclear. Serine/arginine-rich splicing factor 1 (SRSF1) affects the development and progression of cardiovascular disease by selectively splicing downstream signaling proteins. The present study is designed to determine whether PRMT1 is involved in MH by regulating SRSF1 and, if so, to explore the underlying mechanisms. Adult male mice and H9C2 cardiomyocytes are treated with isoprenaline (ISO) to establish MH models. The expression levels of PRMT1 are significantly decreased in the ISO-induced MH models, and inhibiting PRMT1 worsens MH, whereas overexpression of PRMT1 ameliorates MH. SRSF1 serves as the downstream target of PRMT1, and its expression is markedly elevated in MH. Moreover, SRSF1 increases the mRNA expressions of CaMKIIδ A and CaMKIIδ B, decreases the mRNA expression of CaMKIIδ C by altering the selective splicing of CaMKIIδ, and further participates in MH. In addition, there is an interaction between PRMT1 and SRSF1, whereby PRMT1 reduces the phosphorylation level of SRSF1 via methylation, thus further altering its functional activity and eventually improving MH. Our present study demonstrates that PRMT1 relieves MH by methylating SRSF1, which is expected to provide a new theoretical basis for the pathogenic mechanism of MH and potential drug targets for reducing MH and associated cardiovascular disease.
心肌肥厚（MH）是导致严重心血管疾病的一个重要因素。先前的研究表明，特异性缺失蛋白质精氨酸甲基转移酶1（PRMT1）会导致心肌肥厚，但确切机制仍不清楚。富含丝氨酸/精氨酸的剪接因子1（SRSF1）通过选择性剪接下游信号蛋白影响心血管疾病的发生和发展。本研究旨在确定PRMT1是否通过调节SRSF1参与心肌肥厚，如果是，则探索其潜在机制。用异丙肾上腺素（ISO）处理成年雄性小鼠和H9C2心肌细胞以建立心肌肥厚模型。在ISO诱导的心肌肥厚模型中，PRMT1的表达水平显著降低，抑制PRMT1会加重心肌肥厚，而PRMT1的过表达则可改善心肌肥厚。SRSF1是PRMT1的下游靶点，其在心肌肥厚中表达明显升高。此外，SRSF1通过改变CaMKIIδ的选择性剪接增加CaMKIIδ A和CaMKIIδ B的mRNA表达，降低CaMKIIδ C的mRNA表达，并进一步参与心肌肥厚。此外，PRMT1与SRSF1之间存在相互作用，即PRMT1通过甲基化降低SRSF1的磷酸化水平，从而进一步改变其功能活性并最终改善心肌肥厚。我们目前的研究表明，PRMT1通过甲基化SRSF1减轻心肌肥厚，这有望为心肌肥厚的发病机制提供新的理论基础，并为减轻心肌肥厚及相关心血管疾病提供潜在的药物靶点。
