Enhanced Autophagy in GAB1-Deficient Vascular Endothelial Cells Is Responsible for Atherosclerosis Progression

Qian, Xiaohong; Wang, Han; Wang, Yuli; Chen, Jiaquan; Guo, Xiaojia; Deng, Hongbin

doi:10.3389/fphys.2020.559396

Cited by 9 publications

(9 citation statements)

References 36 publications

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“…The aforementioned studies demonstrated that vascular endothelial cell dysfunction is an important factor leading to AS progression and adverse outcomes. HUVEc cells are often used as the cellular model of AS in previous studies (26)(27)(28). In the present study, OX-LdL induced inflammation and injury, and KLF5 interference inhibited the inflammatory response and improved the function of HUVEcs induced by OX-LdL.…”

Section: Discussionsupporting

confidence: 53%

KLF5/LINC00346/miR‑148a‑3p axis regulates inflammation and endothelial cell injury in atherosclerosis

Wang

Huang

et al. 2021

Int J Mol Med

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Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, which are related to high morbidity and mortality rates. The present study aimed to investigate the role of the Krüppel-like factor 5 (KLF5)/LINc00346/miR-148a-3p loop in AS. The expression levels of KLF5 in serum and of KLF5/LINc00346/miR-148a-3p in human umbilical vein endothelial cells (HUVEcs) were detected by RT-qPcR analysis. The protein expression levels of KLF5, phosphorylated (p-)endothelial nitric oxide synthase (eNOS) and eNOS in HUVEcs were analyzed by western blot analysis. changes in the levels of TNF-α, IL-1β, IL-6 and nitric oxide (NO) were determined in the supernatant through the application of available commercial kits. The binding of KLF5 to the promoter region of LINC00346 was verified by chromatin immunoprecipitation (chIP)-PcR assay. The combinatory interaction between KLF5 and LINc00346, LINc00346 and miR-148a-3p, and miR-148a-3p and KLF5 was confirmed by luciferase reporter assay. The results revealed that KLF5 expression was increased in the serum of patients with AS and also in oxidized low-density lipoprotein (OX-LdL)-stimulated HUVEcs. The transcription factor KLF5 promoted the transcription of LINc00346. KLF5 interference or LINc00346 interference inhibited the expression of inflammatory factors and functional injury in OX-LdL-stimulated HUVEcs. LINc00346 functioned as a sponge of miR-148a-3p. miR-148a-3p overexpression inhibited the expression of inflammatory factors and functional injury in OX-LdL-stimulated HUVEcs and miR-148a-3p targeted KLF5 expression. On the whole, the present study demonstrates that KLF5 interference induces the downregulation of LINC00346 and also inhibits inflammation and functional injury in OX OX-LdL-stimulated HUVEcs by upregulating miR-148a-3p expression.FANGFANG WANG, JIYONG GE, SHENGLAN HUANG, cHANGLE ZHOU, ZIKAI SUN, YING SONG, YAJING XU and YUAN JI department of cardiovascular disease, changzhou No.

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Section: Discussionsupporting

confidence: 53%

KLF5/LINC00346/miR‑148a‑3p axis regulates inflammation and endothelial cell injury in atherosclerosis

Wang

Huang

et al. 2021

Int J Mol Med

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“…Qian et al found that excessive autophagy activated by GAB1 deficiency, a docking/scaffolding adaptor protein, inhibited the proliferation of HUVECs lines. 56 Madonna et al reported that excessive autophagy could accelerate myocardial cell death leading to autosis. 57 In addition, excessive autophagy was also found to be able to accelerate the rupture of atherosclerotic plaque in AS patients.…”

Section: Discussionmentioning

confidence: 99%

N‐acetylneuraminic acid modulates SQSTM1/p62 sialyation‐mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice

Chen,

Qiu,

Chen

et al. 2023

IUBMB Life

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Sialic acid (SIA) has been reported to be a risk factor for atherosclerosis (AS) due to its high plasma levels in such patients. However, the effect of increasing SIA in circulation on endothelial function during AS progression remains unclear. In the present study, ApoE−/− mice and endothelial cells line (HUVEC cells) were applied to investigate the effect of SIA on AS progression and its potential molecular mechanism. In vivo, mice were injected intraperitoneally with Neu5Ac (main form of SIA) to keep high‐level SIA in circulation. ORO, H&E, and Masson staining were applied to detect the plaque progression. In vitro, HUVECs were treated with Neu5Ac at different times, CCK‐8, RT‐PCR, western blot, and immunoprecipitation methods were used to analyze its effects on endothelial function and the potential involved mechanism. Results from the present study showed that high plasma levels of Neu5Ac in ApoE−/− mice could aggravate the plaque areas as well as increase necrotic core areas and collagen fiber contents. Remarkably, Neu5Ac levels in circulation displayed a positive correlation with AS plaque areas. Furthermore, results from HUVECs showed that Neu5Ac inhibited cells viability in a time/dose‐dependent manner, by then induced the activation of inflammation makers such as ICAM‐1 and IL‐1β. Mechanism study showed that the activation of excessive autophagy medicated by SQSTM1/p62 displayed an important role in endothelium inflammatory injury. Neu5Ac could modify SQSTM1/p62 as a sialylation protein, and then increase its level with ubiquitin binding, further inducing ubiquitination degradation and being involved in the excessive autophagy pathway. Inhibition of sialylation by P‐3Fax‐Neu5Ac, a sialyltransferase inhibitor, reduced the binding of SQSTM1/p62 to ubiquitin. Together, these findings indicated that Neu5Ac increased SQSTM1/p62‐ubiquitin binding through sialylation modification, thereby inducing excessive autophagy and subsequent endothelial injury. Inhibition of SQSTM1/p62 sialylation might be a potential strategy for preventing such disease with high levels of Neu5Ac in circulation.

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“…Expression of ERRFI1 190 , ALOX12 191 , SOCS5 192 , DDIT4 193 , DUSP4 194 , IL6ST 195 , DUSP1 196 , SMAD1 197 , NCL (nucleolin) 198 , METTL14 199 , FMOD (fibromodulin) 200 , CYGB (cytoglobin) 201 , UNC5A 202 and TAAR9 203 are believed to be associated with diabetic nephropathy. Genes include FAP (fibroblast activation protein alpha) 204 , EYA4 205 , BCL9 206 , IRF2BP2 207 , EGR3 208 , GADD45B 209 , DMD (dystrophin) 210 , LSR (lipolysis stimulated lipoprotein receptor) 211 , DLL4 212 , SUN2 213 , SOS1 214 , PIK3CA 215 , GAMT (guanidinoacetate N -methyltransferase) 216 , RBM47 217 , HSP90AA1 218 , GAB1 219 , S1PR1 220 , EDNRB (endothelin receptor type B) 221 , NFKBIA (NFKB inhibitor alpha) 222 , GJA1 223 , GADD45G 224 , PHLDA1 225 , CMPK2 226 , FIGN (fidgetin, microtubule severing factor) 227 , KCNJ2 228 , ABCC9 229 , DIRAS3 230 , EPHX1 231 , RAB4A 232 , UBIAD1 233 , CASQ2 234 , TTN (titin) 235 , KCNH1 236 , JPH2 237 , OXGR1 238 , UCHL1 239 , SERPINA3 240 , MMP28 241 , ADAMTS2 242 , P2RY1 243 , CSF2RA 244 , MYO1F …”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

Pujar¹,

Vastrad²,

Kavatagimath

et al. 2022

Sci Rep

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Type 1 diabetes mellitus (T1DM) is a metabolic disorder for which the underlying molecular mechanisms remain largely unclear. This investigation aimed to elucidate essential candidate genes and pathways in T1DM by integrated bioinformatics analysis. In this study, differentially expressed genes (DEGs) were analyzed using DESeq2 of R package from GSE162689 of the Gene Expression Omnibus (GEO). Gene ontology (GO) enrichment analysis, REACTOME pathway enrichment analysis, and construction and analysis of protein–protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network, and validation of hub genes were performed. A total of 952 DEGs (477 up regulated and 475 down regulated genes) were identified in T1DM. GO and REACTOME enrichment result results showed that DEGs mainly enriched in multicellular organism development, detection of stimulus, diseases of signal transduction by growth factor receptors and second messengers, and olfactory signaling pathway. The top hub genes such as MYC, EGFR, LNX1, YBX1, HSP90AA1, ESR1, FN1, TK1, ANLN and SMAD9 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Receiver operating characteristic curve (ROC) analysis confirmed that these genes were significantly associated with T1DM. In conclusion, the identified DEGs, particularly the hub genes, strengthen the understanding of the advancement and progression of T1DM, and certain genes might be used as candidate target molecules to diagnose, monitor and treat T1DM.

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Enhanced Autophagy in GAB1-Deficient Vascular Endothelial Cells Is Responsible for Atherosclerosis Progression

Cited by 9 publications

References 36 publications

KLF5/LINC00346/miR‑148a‑3p axis regulates inflammation and endothelial cell injury in atherosclerosis

KLF5/LINC00346/miR‑148a‑3p axis regulates inflammation and endothelial cell injury in atherosclerosis

N‐acetylneuraminic acid modulates SQSTM1/p62 sialyation‐mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

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