The sodium pump Na+/K+-ATPase (NKA), an enzyme ubiquitously expressed in various tissues and cells, is a critical player in maintaining cellular ion homeostasis. Dysregulation of α1 subunit of NKA (NKAα1) has been associated with cardiovascular and metabolic disorders, yet the exact role of NKAα1 in diabetes-induced endothelial malfunction remains incompletely understood. The NKAα1 expression and NKA activity were examined in high-glucose (HG)-exposed endothelial cells (ECs) and mouse aortae, as well as in high-fat-diet (HFD)-fed mice. Acetylcholine (Ach) was utilised to assess endothelium-dependent relaxation (EDR) in isolated mouse aortae. We found that both NKAα1 protein and mRNA levels were significantly downregulated in the aortae of HFD-fed mice, and HG-incubated mouse aortae and ECs. Gain- and loss-of-function experiments revealed that NKAα1 preserves EDR by mitigating oxidative/nitrative stresses in ECs. Overexpression of NKAα1 facilitated EC viability, migration, and angiogenesis by inhibiting the overproduction of superoxide and peroxynitrite. Mechanistically, dysfunctional NKAα1 impaired autophagy process, and prevented the transfer of acyl-CoA synthetase long-chain family member 4 (ACSL4) to the lysosome for degradation, thereby resulting in lipid peroxidation and ferroptosis in ECs. Induction of ferroptosis and inhibition of the autophagy-lysosome pathway blocked the protective effects of NKAα1 on EDR. Eventually, we identified Hamaudol as a potent activator of NKAα1 by restraining the phosphorylation and endocytosis of NKAα1, restoring EDR in obese diabetic mice. Overall, NKAα1 facilitates the autophagic degradation of ACSL4 via the lysosomal pathway, preventing ferroptosis and oxidative/nitrative stress in ECs. NKAα1 may serve as an attractive candidate for the management of vascular disorders associated with diabetes.
Lu Z, Zheng S, Liu C, et al. S100A7 as a potential diagnostic andprognostic biomarker of esophageal squamous cellcarcinoma promotes M2 macrophage infiltrationand angiogenesis. Clin Transl Med. 2021;11:e459. doi: 10.1002/ctm2.459
The reason for the correction:
We proofread the entire article and found that the Western Blot band of the p65 protein in the S100A7 siRNA silencing group in Figure 3H on page 6 accidentally used the same band as the p65 protein in the S100A7 siRNA silencing group in Figure 3G during the editing process.
The western Blot band of p65 protein in the S100A7 siRNA silencing group in Figure 3H that needs errata is marked with a red block below.
Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation.
Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuated pulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis.
The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment.
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