PDF(Pubmed)
Abstract：
Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM can significantly contribute to enhancing its prevention and treatment strategies. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Functionally, inhibition of Kat2a effectively ameliorated high glucose-induced cardiomyocyte injury both in vitro and in vivo by suppressing ferroptosis. Mechanistically, Demethylase alkB homolog 5 (Alkbh5) was found to reduce m6A methylation levels on Kat2a mRNA, leading to its upregulation. YTH domain family 2 (Ythdf2) played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing Tfrc and Hmox1 expression via enhancing the enrichment of H3K27ac and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.
摘要：
糖尿病心肌病(DCM)是一种常见的心肌微血管并发症,发病机制复杂。研究DCM的发病机制有助于加强其预防和治疗策略。我们的研究揭示了赖氨酸乙酰转移酶2A（Kat2a）在DCM中的表达上调，伴随着N6-甲基腺苷（m6A）修饰的Kat2amRNA水平的降低。我们的研究揭示了赖氨酸乙酰转移酶2A（Kat2a）在DCM中的表达上调，伴随着N6-甲基腺苷（m6A）修饰的Kat2amRNA水平的降低。功能上,抑制Kat2a可通过抑制铁凋亡在体外和体内有效改善高糖诱导的心肌细胞损伤。机械上,发现脱甲基酶alkB同源物5（Alkbh5）可降低Kat2amRNA上的m6A甲基化水平，导致其上调。YTH结构域家族2（Ythdf2）作为m6A阅读蛋白在介导Kat2amRNA降解中起着至关重要的作用。此外，Kat2a通过增强H3K27ac和H3K9ac在其启动子区域的富集，通过增加Tfrc和Hmox1的表达来促进铁凋亡。总之,我们的发现揭示了Kat2a-铁性凋亡轴在DCM发病机理中的新作用，为潜在的临床干预提供有价值的见解。
