TET1s deficiency exacerbates oscillatory shear flow-induced atherosclerosis

Abstract

Background: TET1 has been implicated in regulating inflammation and cardiovascular disease, but a newly discovered short isoform of TET1 (termed TET1s) exhibits higher expression in adult tissues than full-length TET1. However, the precise role of TET1 in cardiovascular disease remains undefined. Methods and Results: Based on TET1 -/-knockout mice (with deletion of both TET1 and TET1s ) and TET1 cs/cs mice (with deletion of only TET1), we found that TET1s deletion in TET1 -/-mice resulted in more serious atherosclerotic lesions in the whole aorta than TET1cs/cs in the ApoE -/-background mice fed a high-fat diet. Atherosclerotic lesions with Oil red staining were dramatically localized in the aortic arch, abdominal aorta and ligated LCA, where they were exposed to OSS. Furthermore, the OSS-induced depression of TET1s in vitro and in vivo increased inflammatory cell and red blood cell infiltration into the subendothelial layer by impairing the vascular intimal barrier. TET1s upregulation enhanced vascular endothelial barrier function by increasing gap protein connexin 40 (CX40) expression as measured by RNA-seq and was confirmed by CX40 knockdown. TET1s interaction with Sin3a increased the global and CX40 promoter histone H3K27 acetylation levels, but not DNA methylation, to induce CX40 expression. Conclusions: These data demonstrate the unexpected discovery that laminar shear stress induces TET1s expression to protect the vascular endothelial barrier by increasing CX40 expression in ECs and that TET1s overexpression may be the core step for OSS-induced atherosclerosis therapy.

Universal cell membrane camouflaged nano-prodrugs with right-side-out orientation adapting for positive pathological vascular remodeling in atherosclerosis

“…To assess the extent of AS, the cells or aorta were subjected to ORO staining, following a previously established protocol. 49 A stock ORO solution (Sigma-Aldrich) was prepared by dissolving 150 mg of ORO powder in 50 mL of isopropanol (Sigma-Aldrich). Firstly, the cells or aorta were fixed with 4% PFA to preserve their structural integrity, and washed with 60% isopropanol to remove any residual fixative and prepare them for staining.…”

DNA demethylation in the hypothalamus promotes transcription of Agtr1a and Slc12a2 and hypertension development

“…The membrane was then incubated overnight at 4 °C with the following primary antibodies diluted in in TBST: rabbit anti-DNMT1 (1:500, #24206-1-AP, Proteintech Group, Inc), rabbit anti-DNMT3A (1:1000, #3598S, Cell Signaling Technology), rabbit anti-DNMT3B (1:1000, #72335, Cell Signaling Technology), rabbit anti-MeCP2 (1:1000, #C15310088, Diagenode), rabbit anti-TET1 (1:500, #GTX124207, GeneTex, Inc), rabbit anti-TET2 (1:500, #C15410255, Diagenode Inc), and mouse anti-TET3 (1:1000, #61395, Active Motif). The specificity of these primary antibodies has been previously validated ( 66 , 67 , 68 , 69 , 70 , 71 , 72 ). For the protein loading control, a rabbit anti-GAPDH antibody (1:1000, #5174S, Cell Signaling Technology) was used.…”

Spontaneously Right‐Side‐Out‐Orientated Coupling‐Driven ROS‐Sensitive Nanoparticles on Cell Membrane Inner Leaflet for Efficient Renovation in Vascular Endothelial Injury

“…Permeability Experiment: The permeability experiment was performed as previously described. [49] Mouse samples were injected with 5 mg kg −1 1% Evans blue (Sigma, USA). Then, the samples were anesthetized via intraperitoneal injection with pentobarbital sodium.…”