Jing-Ting Mai

Altered serum levels of IL-33 in patients with advanced systolic chronic heart failure: correlation with oxidative stress

BackgroundInterleukin-33 (IL-33) has been linked to chronic heart failure (CHF) in animal studies, but data on serum IL-33 levels in human CHF are not available. We analyzed levels of IL-33 in serum, and investigated the possible role of IL-33 in oxidative stress.MethodsA total of 191 subjects with advanced systolic CHF (CHF group), 175 patients with pre-existing cardiac diseases but no CHF (non-CHF group), and 177 healthy controls (HC group) were enrolled. Serum levels of IL-33, soluble ST2 (sST2) and N-terminal-pro-brain natriuretic peptide (NT-proBNP), malondialdehyde (MDA) content, erythrocyte superoxide dismutase (eSOD) activity, as well as left ventricular ejection fraction (LVEF), were determined. The exact form of IL-33 in serum was identified. Effects of IL-33 and sST2 on MDA content and SOD activity in angiotensin (Ang II)-stimulated AC16 cells were assessed.ResultsSerum levels of IL-33 and sST2 were elevated in CHF patients, whereas IL-33/sST2 ratios were decreased. In CHF patients, pre-existing cardiac diseases and medications used upon hospital admission did not affect IL-33 concentrations or the IL-33/sST2 ratio. Full-length IL-33, which could not be detected in serum from HC and barely detected in non-CHF patients, was significantly up-regulated in CHF patients. IL-33 levels were positively correlated with markers of CHF severity. IL-33/sST2 ratios were slightly and negatively related to MDA concentrations. IL-33 directly reduced MDA and enhanced SOD activity in Ang II-stimulated AC16 cells, which were greatly attenuated by sST2.ConclusionsSerum levels of IL-33, especially the full-length form, were elevated in CHF patients whereas IL-33 bioactivity was reduced. In advanced CHF, IL-33 may exert anti-oxidation effects, which may be overwhelmed by concurrently elevated levels of sST2.

Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway

AIMS Hydrogen sulfide (H2S) ameliorates cardiac fibrosis in several models by suppressing endoplasmic reticulum (ER) stress. Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of cardiac fibrosis. Therefore, we investigated whether H2S could attenuate EndMT by suppressing ER stress. MAIN METHODS ER stress was induced by tunicamycin (TM) and thapsigargin (TG) and inhibited by 4-phenylbutyrate (4-PBA) in human umbilical vein endothelial cells (HUVECs). ER stress and EndMT were measured by Western blot, Real-Time PCR and immunofluorescence staining. Inhibition Smad2 and Src pathway were performed by specific inhibitors and siRNA. Ultrastructural examination was detected by transmission electron microscope. The functions of HUVECs were investigated by cell migration assay and tube formation in vitro. KEY FINDINGS Under ER stress, the expression of endothelial marker CD31 significantly decreased while mesenchymal markers α-SMA, vimentin and collagen 1 increased which could be inhibited by 4-PBA. Moreover, HUVECs changed into a fibroblast-like appearance with the activation of Smad2 and Src kinase pathway. After inhibiting Src pathway, EndMT would be significantly inhibited. TM reduced H2S levels in cell lysate and H2S pretreatment could preserve endothelial cell appearance with decreased ER stress and ameliorated dilation of ER. H2S could also downregulate the mesenchymal marker expression, and upregulate the endothelial markers expression, accompanied with the suppression of Src pathway. Moreover, H2S partially restored the capacity of migration and tube formation in HUVECs. SIGNIFICANCE These results revealed that H2S could protect against ER stress-induced EndMT through Src pathway, which may be a novel role for the cardioprotection of H2S.

C-reactive protein promotes vascular endothelial dysfunction partly via activating adipose tissue inflammation in hyperlipidemic rabbits

BACKGROUND Endothelial dysfunction is the basic and original sign of atherogenesis. Some evidences show that C-reactive protein (CRP) and perivascular adipose tissue (PVAT) play a pivotal role in atherosclerosis. However, the effects of CRP on atherosclerosis and the related mechanisms require elucidation. METHODS The levels of basic total cholesterol, low-density lipoprotein cholesterol, triglyceride, CRP, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO) and endothelin-1 (ET-1) were respectively measured in rabbits, endothelium-dependent vasorelaxation function was also evaluated. Animals were randomly divided into two groups: PVAT(-) and PVAT(+) group (removing or keeping pericarotid adipose tissue (PCAT)). Both of the two groups were exposed to a high-fat diet for six-week, and then sustained CRP treatment was performed for a week, at this time point all the above parameters were remeasured. In addition, mRNA and protein expression of TNF-α, IL-6, and macrophage chemoattractant protein-1 (MCP-1) were respectively evaluated by Polymerase Chain Reaction and immunoblotting in PCAT and cultured adipocytes treated by CRP. RESULTS High-fat diet greatly increased the serum lipids and inflammatory markers, induced endothelial dysfunction and imbalance between NO and ET-1, increased mRNA and protein expression of TNF-α, IL-6, MCP-1 and enhanced macrophage infiltration of PCAT. CRP treatment could further promote macrophage infiltration of PVAT, induce the imbalance between NO and ET-1, aggravate endothelial dysfunction especially in PVAT(+) arteries, and could also enhance the above-mentioned mRNA and protein expression in PCAT and cultured adipocytes. CONCLUSIONS CRP could significantly promote endothelial dysfunction in high-fat diet rabbits especially in PVAT(+) groups, which may be partly mediated by activating inflammatory reaction of adipose tissue.

Clinical effectiveness of telemedicine for chronic heart failure: a systematic review and meta-analysis

Telemedicine interventions may be associated with reductions in hospital admission rate and mortality in patients with heart failure (HF). The present study is an updated analysis (as of June 30, 2016) of randomized controlled trials, where patients with HF underwent telemedicine care or the usual standard care. Data were extracted from 39 eligible studies for all-cause and HF-related hospital admission rate, length of stay, and mortality. The overall all-cause mortality (pooled OR=0.80, 95% CI 0.71 to 0.91, p<0.001), HF-related admission rate (pooled OR=0.63, 95% CI 0.53 to 0.76, p<0.001), and HF-related length of stay (pooled standardized difference in means=−0.37, 95% CI −0.72 to −0.02, p=0.041) were significantly lower in the telemedicine group (teletransmission and telephone-supported care), as compared with the control group. In subgroup analysis, all-cause mortality (pooled OR=0.69, 95% CI 0.56 to 0.86, p=0.001), HF-related admission rate (OR=0.61, 95% CI 0.42 to 0.88, p=0.008), HF-related length of stay (pooled standardized difference in means=−0.96, 95% CI −1.88 to −0.05, p=0.039) and HF-related mortality (OR=0.68, 95% CI 0.54 to 0.85, p=0.001) were significantly lower in the teletransmission group, as opposed to the standard care group, whereas only HF-related admission rate (OR=0.64, 95% CI 0.52 to 0.79, p<0.001) was lower in the telephone-supported care group. Overall, telemedicine was shown to be beneficial, with home-based teletransmission effectively reducing all-cause mortality and HF-related hospital admission, length of stay and mortality in patients with HF.

Angiotensin II-Derived Reactive Oxygen Species Promote Angiogenesis in Human Late Endothelial Progenitor Cells Through Heme Oxygenase-1 via ERK1/2 and AKT/PI3K Pathways

Angiotensin II (Ang II), the main component of renin-angiotensin system, could mediate pathogenic angiogenesis in cardiovascular disorders. Late endothelial progenitor cells (EPCs) possess potent self-renewal and angiogenic potency superior to early EPCs, but few study focused on the cross-talk between Ang II and late EPCs. We observed that Ang II could increase reactive oxygen species (ROS) and promote capillary formation in late EPCs. Ang II-derived ROS could also upregulate heme oxygenase-1 (HO-1) expression, and treating late EPCs with HO-1 small interfering RNA or heme oxygenase inhibitor (HO inhibitor) could inhibit Ang II-induced tube formation and increase ROS level and apoptosis rate. In addition, PD98059 and LY294002 pretreatment attenuated Ang II-induced HO-1 expression. Accordingly, Ang II-derived ROS could promote angiogenesis in late EPCs by inducing HO-1 expression via ERK1/2 and AKT/PI3K pathways, and we believe HO-1 might be a promising intervention target in EPCs due to its potent proangiogenic, antioxidant, and antiapoptosis potentials.

Dyssynchronous Pacing Triggers Endothelial-Mesenchymal Transition Through Heterogeneity of Mechanical Stretch in a Canine Model

BACKGROUND Endothelial-mesenchymal transition (EndMT) plays a pivotal role in cardiac fibrosis. However, it is unclear whether EndMT is involved in dyssynchronous heart failure (DHF). METHODS AND RESULTS Twelve dogs received 3-week rapid right ventricular pacing (RVP) to develop DHF and then were randomly divided into a RVP group (n=6; RVP for another 3 weeks) and a biventricular pacing (BiVP) group (n=6; BiVP for 3 weeks), and another 6 dogs were in the control group. Contractile function in BiVP group was a little better than that in RVP group (P<0.05), but significant heart failure remained in 2 groups. RVP induced more significant cardiac fibrosis and higher collagen 1A2 expression in the left ventricular lateral wall (late-contracting and high-stress) than that in the anterior wall, and for those in the BiVP group, it was much lower. CD31, S100A4, α-smooth muscle actin and collagen 1A2 were used to evaluate EndMT. EndMT levels, transforming growth factor-β (TGF-β)/snail signaling, collagen 1A2 and integrin β1 expression were much higher in the endothelial cells from the RVP lateral wall than that from BiVP. In this in vitro study, cyclic stretch could independently induce EndMT and enhance the pro-EndMT effect of TGF-β in HUVECs, which could be partly blocked by integrin β1 siRNA. CONCLUSIONS RVP-induced DHF could aggravate fibrosis due to regional heterogeneity of mechanical stress, and it was better in the BiVP group where mechanical stress-induced EndMT might play a pivotal role through the integrin β1 pathway.

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-β (TGF-β) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-β. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis.

The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway

BACKGROUND AND AIMS We examined whether the inflammation resolution mediator lipoxin A4 (LXA4) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA4 biosynthesis in atherogenesis. METHODS LXA4 levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays. RESULTS Circulating LXA4 levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA4 levels were much lower in rabbit atherosclerotic vessel walls. Interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-γ, TNF-α, and C-reactive protein), LXA4 synthesis decreased significantly in foam cells. LXA4 dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA4 receptor antagonist BOC-2. LXA4 also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA4 inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential. CONCLUSIONS We found that LXA4 inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA4 were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.