OxLDL induces vascular endothelial cell pyroptosis through miR‐125a‐5p/TET2 pathway

Abstract

Pyroptosis participates in the formation and development of atherosclerosis (As) by promoting inflammatory factor release and is closely related to the stability of atherosclerotic plaque. MicroRNAs can regulate the expression of target genes at the posttranscriptional level. Previous studies have shown that miR-125a-5p increases in hyperlipidemic-hyperglycemic conditions and is involved in apoptosis, but its specific role in pyroptosis and As remains unclear. We propose that miR-125a-5p may be implicated in oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial cells (VECs) pyroptosis and therefore conducted the current study. We observed that miR-125a-5p can inhibit tet methylcytosine dioxygenase 2 (TET2) expression at the posttranscription level, resulting in abnormal DNA methylation, mitochondrial dysfunction, and increased reactive oxygen species production, activated nuclear factor-κB that induces activation of inflammasome and maturation, release of proinflammatory cytokines interleukin (IL)-1β and IL-18, and pyroptosis. Given the role of VECs in vascular physiology, oxLDL-induced VEC pyroptosis may promote the development of As. Our current study reveals a novel pathway associated with pyroptosis program regulation, which comprises miR-125a-5p and TET2 in VECs.Modulation of their expression levels may serve as a potential target for therapeutic strategies of As. K E Y W O R D Satherosclerosis, miR-125a-5p, pyroptosis, ROS, TET2

Transcription Factor p53 Suppresses Tumor Growth by Prompting Pyroptosis in Non-Small-Cell Lung Cancer

“…Programmed cell death was first reported in 1842, which is recognized as an irreversible process involving complex molecular factors or pathways to maintain cellular homeostasis and control diseases in multicellular organisms [28]. Among several programmed cell deaths, pyroptosis is the most recently investigated which is characterized as an inflammatory form of regulated cell death which is triggered by microbial infection, heart attack, stroke, and cancer progression [29]. Pizato et al have reported that pyroptosis is tightly related to breast cancer cell death and further contributes to improved treatment during breast cancer [30].…”

Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus

“…Importantly, an animal experiment has demonstrated that piperine significantly reduced the pyroptosis of tubular epithelial cells, leading to the suppression of LN development in pristane-induced lupus mice [89]. Interestingly, vascular endothelial cells can also be induced to undergo pyroptosis through the miR-125a-5p/TET2 pathway, perhaps explaining one kind of mechanisms in tissue damage in SLE [119]. Surprisingly, caspase-3, generally believed an executioner in apoptosis process, can also cleave GSDME to induce pyroptosis [92].…”

Essential Role of Nonessential Amino Acid Glutamine in Atherosclerotic Cardiovascular Disease

“…Reactive oxygen species (ROS), a marker of oxidative stress, is mainly produced in the mitochondrial electron transport chain during cell metabolism and plays important roles in cell biological behaviors, such as proliferation and apoptosis (Cameron et al, 2019). Recent studies showed that ROS increases the pyroptosis of VEC that contributes to VEC dysfunction and As progression (Wu et al, 2018;Zhaolin et al, 2019). Lowering oxidative stress injury induced by ROS is considered as a promising therapy to inhibit the progression of As (Burtenshaw et al, 2019).…”