N 6 -methyladenosine (m 6 A) is the most prevalent and abundant type of internal post-transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non-coding RNAs and microRNAs, are involved in m 6 A methylation. The biological function of m 6 A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m 6 A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m 6 A modification and is typically made up of methyltransferase-like (METTL)3, METTL14 and Wilms tumor 1-associated protein. Erasers remove methylation by fat mass and obesity-associated protein and ALKB homolog 5. Readers play a role through the recognition of m 6 A-modified targeted RNA. The YT521-B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin-like growth factor 2 mRNA-binding protein serve as m 6 A readers. The m 6 A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post-transcriptional level. The dysregulation of m 6 A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m 6 A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m 6 A modification in CVD and give a brief perspective on its prospective applications in CVD.

The CREATE-ECLA Randomized Controlled TrialThe CREATE-ECLA Trial Group Investigators* See also pp 427 and 489.

BACKGROUND Endothelial dysfunction, a hallmark of diabetes, is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications. However, the underlying mechanisms are still not fully understood. Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases, the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear. AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms. METHODS Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG), interleukin-1β (IL-1β), and ferroptosis inhibitor, and then the cell viability, reactive oxygen species (ROS), and ferroptosis-related marker protein were tested. To further determine whether the p53-xCT (the substrate-specific subunit of system Xc - )-glutathione (GSH) axis is involved in HG and IL-1β induced ferroptosis, HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β. Cell viability, ROS, and ferroptosis-related marker protein were then assessed. In addition, we detected the xCT and p53 expression in the aorta of db/db mice. RESULTS It was found that HG and IL-1β induced ferroptosis in HUVECs, as evidenced by the protective effect of the ferroptosis inhibitors, Deferoxamine and ferrostatin-1, resulting in increased lipid ROS and decreased cell viability. Mechanistically, activation of the p53-xCT-GSH axis induced by HG and IL-1β enhanced ferroptosis in HUVECs. In addition, a decrease in xCT and the presence of de-endothelialized areas were observed in the aortic endothelium of db/db mice. CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.

No abstract

No abstract