Objectives Arterial wall inflammation and remodelling are the characteristic features of Takayasu’s arteritis (TAK). It has been proposed that vascular smooth muscle cells (VSMCs) are the main targeted cells of inflammatory damage and participate in arterial remodelling in TAK. Whether VSMCs are actively involved in arterial wall inflammation has not been elucidated. Studies have shown that cellular senescence in tissue is closely related to local inflammation persistence. We aimed to investigate whether VSMCs senescence contributes to vascular inflammation and the prosenescent factors in TAK. Methods VSMCs senescence and senescence-associated secretory phenotype were detected by histological examination, bulk RNA-Seq and single-cell RNA-seq conducted on vascular surgery samples of TAK patients. The key prosenescent factors and the downstream signalling pathway were investigated in a series of in vitro and ex vivo experiments. Results Histological findings, primary cell culture and transcriptomic analyses demonstrated that VSMCs of TAK patients had the features of premature senescence and contributed substantially to vascular inflammation by upregulating the expression of senescence-associated inflammatory cytokines. IL-6 was found to be the critical cytokine that drove VSMCs senescence and senescence-associated mitochondrial dysfunction in TAK. Mechanistically, IL-6-induced non-canonical mitochondrial localisation of phosphorylated STAT3 (Tyr705) prevented mitofusin 2 (MFN2) from proteasomal degradation, and subsequently promoted senescence-associated mitochondrial dysfunction and VSMCs senescence. Mitochondrial STAT3 or MFN2 inhibition ameliorated VSMCs senescence in ex vivo cultured arteries of TAK patients. Conclusions VSMCs present features of cellular senescence and are actively involved in vascular inflammation in TAK. Vascular IL-6-mitochondrial STAT3-MFN2 signalling is an important driver of VSMCs senescence.

Background: Layer-specific speckle-tracking echocardiography (STE) is a noninvasive approach that assesses subclinical left ventricular dysfunction. We aimed to investigate the (I) alteration of layer-specific STE parameters and the dyssynchrony index; and (II) the disease parameters associated with layer-specific STE change in drug-naïve patients with new-onset systemic lupus erythematosus (SLE) without cardiac symptoms. Methods: Thirty-five drug-naïve patients with new-onset SLE and twenty-five healthy controls were enrolled. All individuals received both conventional echocardiographic and two-dimensional STE assessment. The data of layer-specific global longitudinal strain (GLS), global circumferential strain (GCS), and peak systolic dispersion (PSD) were acquired in layer-specific STE. Results: All patients had a normal left ventricular ejection fraction (LVEF)(mean LVEF: 58%) and conventional echocardiographic parameters were comparable between patients and controls. Decreased layer-specific GLS and elevated PSD were observed in SLE patients (whole layer GLS: −17.6%±3.0% versus −19.3%±2.6%, P=0.02; endocardial GLS: −20.0%±3.2% versus −22.1%±3.0%, P=0.01; epicardial GLS: −15.6%±2.7% versus −16.8%±2.4%, P=0.04; PSD: 41.0±18.9 versus 28.8±10.1 msec, P=0.007). In contrast, there was no difference in layer-specific GCS at three different levels between patients and controls (P>0.05). More severely impaired GLS was observed in patients with higher disease activity, high-risk antiphospholipid antibody (aPL) profile, or renal involvement. The PSD was increased in patients with higher disease activity or a high-risk aPL profile. Correlational analysis showed that GLS at three layers and PSD correlated with high-sensitivity C-reactive protein (hsCRP) levels (whole GLS: r=0.662, P<0.001; endocardial GLS: r=0.637, P<0.001; epicardial GLS: r=0.658, P<0.001; PSD: r=0.390, P=0.021). PSD correlated with epicardial GLS (r=0.360, P=0.047), when treating the hsCRP level, renal involvement, aPL profile, and disease activity as control variables. Multivariate regression showed the hsCRP level and epicardial GLS were predictors of layer-specific GLS impairment and elevated PSD, respectively. Conclusions: Drug-naive patients with new-onset SLE are likely to have subclinical GLS impairment and left ventricular dyssynchrony, even in the presence of normal LVEF. SLE-related risk factors are associated with these dysfunctions.

Our previous work identified several differentially expressed miRNAs (DEmiRNAs) in plasma exosomes from Takayasu’s arteritis (TAK) patients. This study aimed to validate these findings and explore the correlation between DEmiRNAs and clinical parameters in untreated TAK. Plasma exosomes were isolated from 30 untreated TAK patients and 20 healthy controls. qPCR was used to quantify miR-34a-5p, miR-143-3p, miR-22-3p, miR-200c-3p, and miR-21-5p expression. Correlations between miRNA levels, clinical data, inflammation markers, and T helper cell frequencies were analyzed. The target genes of validated DEmiRNAs were identified using mirDIP, and pathway enrichment analysis was performed using GO/KEGG. The effect of validated DEmiRNAs on the MAPK pathway and proliferation in human aortic endothelial cells (HAECs) was investigated in vitro. Only miR-200c-3p expression was validated as significantly downregulated in plasma exosomes from untreated TAK patients. Lower miR-200c-3p levels correlated negatively with ITAS-2010 scores and were associated with relapsed disease. MiR-200c-3p levels also negatively correlated with circulating Th17.1 cell frequencies. In vitro, the TAK exosome treatment activated ERK1/2 and JNK pathways and promoted HAEC proliferation, which was inhibited by the miR-200c-3p mimic. The pathway enrichment analysis showed that the MAPK pathway may be involved. This study confirms the reduced miR-200c-3p expression in plasma exosomes from TAK patients, suggesting its potential as a biomarker for vascular inflammation. MiR-200c-3p may exert protective effects in TAK by suppressing MAPK pathway activation and EC proliferation.

Background Layer-specific speckle-tracking echocardiography (STE) is a noninvasive approach assessing subclinical left ventricular (LV) dysfunction. We aimed to investigate: (I) layer‐specific strain and dyssynchrony index alteration; (II) disease parameters associated with layer-specific STE change; (III) effects of hydroxychloroquine (HCQ) therapy on layer-specific STE parameters in drug-naïve patients with new-onset systemic lupus erythematosus (SLE) without cardiac symptoms. Methods 35 drug-naïve patients with new-onset SLE and 25 age-and-sex-matched healthy controls were enrolled. All individuals received both conventional echocardiographic and two-dimensional STE assessment. Layer-specific global longitudinal strain (GLS), global circumferential strain (GCS) and peak systolic dispersion (PSD) were acquired in layer-specific STE. The effect of HCQ monotherapy on GLS parameters and PSD was assessed in 7 SLE patients with stable disease. Results All patients had normal left ventricular ejection fraction (LVEF). Conventional echocardiographic parameters were comparable between patients and controls. Decreased layer-specific GLS and elevated PSD were observed in SLE patients. In contrast, there’s no difference of layer-specific GCS at the basal level, papillary muscle level and apical level between patients and controls. More severely impaired GLS was observed in patients with higher disease activity, high-risk aPL profile or renal involvement. PSD increased in patients with higher disease activity or high-risk aPL profile. Correlational analysis showed that GLS at three layers and PSD correlated with high-sensitivity CRP (hsCRP) levels. PSD correlated with epicardial GLS, when treating hsCRP level, renal involvement, profile of aPL and disease activity as control variables. Multivariate regression showed hsCRP level and epicardial GLS are the predictors of layer-specific GLS impairment and elevated PSD, respectively. No change of GLS at three layers or PSD was observed in the first 6 months of HCQ treatment, compared with baseline. During the second 6 months of HCQ treatment, increase of endocardial GLS and whole layer GLS, and decrease of PSD were detected. There was no change of epicardial GLS during follow-up. Conclusion Drug-naïve patients with new-onset SLE, even having normal LVEF, are likely to have subclinical GLS impairment and LV dyssynchrony. SLE-related risk factors are associated with these dysfunctions. Continuous use of HCQ may provide beneficial effects to the silent cardiac impairment.