Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxininteracting protein-mediated hypoxia-inducible factor-1αpathway

BACKGROUND Extracellular vesicles(EVs)derived from hypoxia-preconditioned(HP)mesenchymal stem cells(MSCs)have better cardioprotective effects against myocardial infarction(MI)in the early stage than EVs isolated from normoxic(NC)-MSCs.However,the cardioprotective mechanisms of HP-EVs are not fully understood.AIM To explore the cardioprotective mechanism of EVs derived from HP MSCs.METHODS We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs(ADSCs)following hypoxia in vitro or MI in vivo,in order to improve the survival of cardiomyocytes(CMs)and restore cardiac function.The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays.MicroRNA(miRNA)sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs.The molecular mechanism of EVs in mediating thioredoxin-interacting protein(TXNIP)was verified by the dual-luciferase reporter assay.Co-immunoprecipitation,western blotting,and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha(HIF-1α)ubiquitination and degradation via the chromosomal region maintenance-1(CRM-1)-dependent nuclear transport pathway.RESULTS HP-EVs derived from MSCs reduced both infarct size(necrosis area)and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo.Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP,an oxidative stress-associated protein.We showed miRNA224-5p,the most upregulated miRNA in HP-EVs,directly combined the 3’untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury.Our results demonstrated that MI triggered TXNIP-mediated HIF-1αubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs,which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI.CONCLUSION The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

Effects of post-dilation on coronary blood flow and MACE events following primary percutaneous coronary intervention in patients with STEMI

Objective:This retrospective cohort study aimed to evaluate the effect of post-dilation on coronary blood flow and MACE events during hospitalization and 1 year follow-up following primary PCI in patients with ST-segment.Methods:419 eligible patients who underwent PPCI due to STEMI between January 2015 and October 2019 were enrolled.The CTFC,final QCA,and the incidence of no-reflow/slow-flow during different procedure moments were assayed.Study end points was to compare two groups of patients with clinical characteristics,compared two groups of patients with the incidence of no-reflow and slow-flow,and the incidence of MACE during hospitalization and 1-year follow-up.Results:The incidence of final no-reflow/slow-flow in the post-dilation group was not significantly higher than that in the non-post-dilation group(24.3%vs.19.4%;p=0.238).There was no significant statistical difference in MACE events during hospitalization,but for the 1-year follow-up,the incidence of Target vessel revascularization and Target lesion revascularization in the post-dilation group was lower than that in the non-post-dilation group.A multivariable logistic regression model revealed that age(OR=1.078,95%CI=1.038-1.120;P<0.001),history of diabetes(OR=3.009,95%CI=1.183-7.654;P=0.021),post-dilation(OR=0.192,95%CI=0.067-0.549;P=0.002)were independently correlated with long-term follow-up of MACE.Conclusion:Post-dilation does not increase poor prognosis during hospitalization,and reduces the incidence of TVR and TLR events during long-term follow-up.

Incidence of congenital heart diseases in Chinese children with non-syndromic congenital blepharoptosis:a prospective observational study of 1053 patients

Background Congenital blepharoptosis(CBP)may be part of a large spectrum of birth defects presenting with other ocular or systemic conditions.Therefore,the aim of the study was to investigate the incidence of congenital heart diseases(CHD)in CBP children not associated with specific syndromes.Methods A total of 1053 Chinese children diagnosed with non-syndromic CBP were consecutively enrolled and their cardiac structure was evaluated by echocardiography.Results Forty children were identified with CHD.Twenty-four children had one type of structural malformation(simple CHD).Sixteen children had two or more types of structural malformation(complex CHD).CHD and complex CHD were more prevalent in patients with severe or bilateral ptosis.Multivariate analysis revealed that presence of severe ptosis and bilateral ptosis was independently associated with CHD occurrence.Conclusions We found an increased frequency of CHD in CBP children,suggesting a clinical need for routine echocardiography evaluation in CBP,especially in children with severe or bilateral ptosis.