The endothelial dysfunction induced by oxidized low-density lipoprotein (ox-LDL) plays an important role in the pathogenesis of atherosclerosis, which can lead to oxidative stress and inflammation. The role of autophagy in the process of atherosclerosis has drawn increasing attention. The human umbilical vein endothelial cells (HUVECs), whose Ras-related C3 botulinum toxin substrate 1 (Rac1) and Rac3 was knockdown, were used to detect whether the possible molecular mechanisms of Rac1 and Rac3 for anti-inflammatory in endothelial cells was effected by downregulation of autophagy. The HUVECs were incubated with ox-LDL. The inflammatory factors and autophagy proteins were evaluated to ascertain and compare the effect of Rac1 and Rac3 on autophagy. Then, 3-methyladenine (3-MA) as an inhibiter of autophagy was used to detect whether the effect of Rac1 and Rac3 was related to autophagy. ox-LDL-induced cell dysfunction in HUVECs was determined by testing the formation of foam cells, the expression of nuclear factor (NF)-κB and nucleotidebinding oligomerization domain (NOD)-like receptor protein 3 and NF-κB p65 and other inflammatory factors, the release of reactive oxygen species by oxidative stress and the dysfunction of the cytomembrane. And ApoE −/− mice on a high-fat diet were used as an animal model to detect the effect of Rac1 and Rac3 in vivo. The resultsshowed that when Rac1 and Rac3 were decreased in HUVECs, the cell dysfunction caused by ox-LDL was inhibited. If 3-MA was used to inhibit autophagy in Rac1 and Rac3 knockdown cells, the injury induced by ox-LDL on the cells was recovered.These results indicated that the effect of Rac1 and Rac3 was combined with ox-LDL, which was related to inhibition of autophagy. The effect of Rac3 was more significant than that of Rac1. atherosclerosis, autophagy, endothelial dysfunction, Rac1, Rac3Abbreviations: 3-MA, 3-methyladenine; ApoE, apolipoprotein E; AS, atherosclerosis; CE, cholesterol esterification; DMEM, Dulbecco's modified Eagle's media; DOX, doxycycline; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; H&E stain, hematoxylin and eosin stain; HDL-C, high-density lipid cholesterol; HUVECs, human umbilical vein endothelial cells; IL-1β, interleukin-1β; LDH, lactic dehydrogenase; LDL-C, low-density lipid cholesterol; MMP, mitochondria membrane potential; NLRP3, nuclear factor (NF)-κB and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3; ox-LDL, oxidized low-density lipoprotein; PBS, phosphate buffered saline; Rac, Ras-related C3 botulinum toxin substrate; ROS, reactive oxygen species; shRNA, small hairpin RNA; siRNA, small inhibitor RNA; TC, total cholesterol; TG, triglycerides; VCAM-1, vascular cell adhesion molecule-1.
Platelet GPVI associated with platelet activation and endothelial inflammation is a vital index for predicting CHD occurrence and severity.
Phosphocreatine (PCr) has been shown to have a cardio-protective effect during cardiopulmonary resuscitation (CPR). However, little is known about its impact on atherosclerosis. In this study, we firstly evaluated the pharmacological effects of PCr on antioxidative defenses and mitochondrial protection against hydrogen peroxide (H2O2) induced human umbilical vascular endothelial cells (HUVECs) damage. Then we investigated the hypolipidemic and antioxidative effects of PCr on hyperlipidemic rat model. Via in vitro studies, H2O2 significantly reduced cell viability and increased apoptosis rate of HUVECs, while pretreatment with PCr abolished its apoptotic effect. PCr could reduce the generation of ROS induced by H2O2. Moreover, PCr could increase the activity of SOD and the content of NO, as well as decrease the activity of LDH and the content of MDA. PCr could also antagonize H2O2-induced up-regulation of Bax, cleaved-caspase3, cleaved-caspase9, and H2O2-induced down-regulation of Bcl-2 and p-Akt/Akt ratio. In addition, PCr reduced U937 cells’ adhesion to H2O2-stimulated HUVECs. Via in vivo study, PCr could decrease MDA, TC, TG and LDL-C levels in hyperlipidemic rats. Finally, different-concentration PCr could increase the leaching of TC, HDL, and TG from fresh human atherosclerotic plaques. In conclusion, PCr could suppress H2O2-induced apoptosis in HUVECs and reduce hyperlipidemia through inhibiting ROS generation and modulating dysfunctional mitochondrial system, which might be an effective new therapeutic strategy to further prevent atherosclerosis.
Pyruvate dehydrogenase complex (PDH) is an important complex of three enzymes that transforms pyruvate into acetyl-CoA, subsequently entering the tricarboxylic acid (TCA) cycle to produce ATP and electron donors. As a key regulator of energy and metabolic homeostasis, PDH is considered a potential therapeutic target of many diseases. On the other hand, the relationship between PDH and obesity is not clear. In this study, peripheral blood of Pdha1 fl/fl Lyz2-Cre and C57BL/6 mice fed a high-fat diet (HFD) was collected and subjected to extensive transcriptome sequencing.Differentially expressed genes (DEGs) were identified. Enrichment of functions and signaling pathways analyses were performed based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the genes selected from RNA sequencing (RNA-seq). Eventually, we found that Pdha1 fl/fl Lyz2-Cre mice were more susceptible to HFD-induced obesity. A total of 302 up-regulated genes and 30 downregulated genes were screened that were differentially expressed between Pdha1 fl/fl Lyz2-Cre mice fed the HFD and the control groups. Furthermore, we verified that significant transcriptional changes in the genes Sgstm1,
Background The detachment of the left atrial appendage(LAA) thrombus is the major cause of cardioembolic stroke(CES)/cardioembolic transient ischemic attack(CETIA). A LAA thrombus is very infrequently detected in the presence of sinus rhythm. Patent foramen ovale(PFO) is another common reason for CES/CETIA, especially among young and middle-aged people.Case Presentation We reported a case of a 46-year-old man who presented with TIAs and was subsequently found with PFO and LAA thrombus despite being in sinus rhythm and basically normal structure and function. Anticoagulant treatment was effective, and there was no recurrence of TIA or stroke.Conclusion LAA thrombus could occur in sinus rhythm and normal structure and function. The PFO may be an innocent bystander in the patient suspected of CES/CETIA. Percutaneous PFO closure should be cautiously chosen.
Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. We found that K73-03 could significantly inhibit the cell viability, migration and colony formation of SMMC-7721 and HepG2 cells in a dose-dependent manner, having a stronger effect on HepG2 cells. Excess ROS was produced when treated with K73-03 compared with the control group. After adding a reactive oxygen scavenger, N-acetyl-L-cysteine (NAC), the expression of ROS was downregulated. For mitochondrial dysfunction, K73-03 could reduce Mitochondrial membrane potential (∆Ψm) and inhibit cell respiration. In mechanism studies, the ratio of Bax/Bcl-2 and the expressions of cleaved-caspase9 and cleaved-caspase3 in HepG2 cells were upregulated after K73-03 treatment, while the ratio of LC3B-II/I and the expression of Beclin1 were also increased. The protein expressions of p-JAK2, p-STAT3, COX-2, p65 and p-65 in K73-03 treated HepG2 cells were downregulated and the nuclear translocation of p65 was inhibited. In our study, K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway.
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