Previous studies have demonstrated that oxidative stress is closely related to aortic dissection (AD). Sestrin2 (Sesn2) is an important antioxidant protein, and this study aimed to investigate ...whether Sesn2 participates in AD and the possible mechanisms.
Sesn2 expression was detected in aortas collected from AD patients and normal donors. In addition, blood samples were collected from AD patients and non-AD (NAD) patients, and the plasma Sesn2 levels were measured. Furthermore, the effects of Sesn2 on angiotensin (Ang) II-induced smooth muscle cell (SMC) apoptosis were investigated in vitro.
Compared with the aortas from normal donors, aortas from AD patients had significantly increased Sesn2. Sesn2 was mainly secreted by macrophages, and low levels were secreted by CD4+ T lymphocytes, but not SMCs. Plasma Sesn2 levels were also increased in AD patients compared with NAD patients. Sesn2 levels were negatively corrected with superoxide dismutase (SOD) levels but positively corrected with malondialdehyde (MDA) levels in AD patients. In co-cultures of macrophages and SMCs, Sesn2 overexpression in macrophages significantly reduced Ang II-induced SMC apoptosis, and this effect could be reversed by Nrf2 silencing.
Sesn2 is increased in both aortas and plasma from AD patients. Sesn2 may alleviate Ang II-induced SMC apoptosis and participate in AD via the Nrf2 pathway. Sesn2 may be a new target in the treatment and prevention of AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Atherosclerosis and its sequelae, such as coronary artery disease (CAD), are the most common diseases worldwide and the leading causes of morbidity and mortality in most countries. Our previous ...studies have shown that circulating secreted frizzled-related protein 4 (SFRP4) levels are increased in patients with CAD. However, the role of SFRP4 in the development of atherosclerosis remains unclear; thus, the purpose of this study was to determine the effect of SFRP4 on high-fat diet (HFD)-induced atherosclerosis and explore the possible mechanisms. In this study, we found for the first time that administration of recombinant SFRP4 alleviates atherosclerosis in ApoE−/− mice by reducing inflammation and oxidative stress. In addition, the anti-atherosclerotic effect of SFRP4 was associated with inhibition of the Wnt/β-catenin signaling pathway, and Wnt1 overexpression abolished the anti-atherosclerotic effects of SFRP4. Taken together, our results highlight the potential beneficial effect of SFRP4 as a therapeutic agent for atherosclerosis and CAD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background. Previous studies demonstrated that the subsets of CD4+ T helper (Th) cells are closely related to vascular diseases, including atherosclerosis and hypertension. This study is aimed at ...investigating the circulating Th1, Th2, Th9, Th17, Th22, and Treg levels in aortic dissection (AD) patients. Methods. Blood samples from AD (n=56) and non-AD (NAD, n=24) patients were collected, and the circulating levels of Th1, Th2, Th9, Th17, Th22, and Treg cells and their transcription factors and functional cytokines were measured by flow cytometric analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays, respectively. In addition, the human aortic vascular smooth muscle cells (HASMCs) were treated with saline, angiotensin II (Ang II), or plasma from AD patients. Results. Compared with the levels in the NAD group, the Th1, Th9, Th17, Th22, and their transcription factor levels were increased and the Th2, Treg, and their transcription factor levels exhibited a decreasing trend in AD patients. In addition, higher IFN-γ, IL-9, IL-17, and IL-22 levels and lower IL-4 and IL-35 levels were observed in AD patients. Simple linear regression analysis and binary logistic regression analysis suggested that Th1/IFN-γ, IL-9, Th17/IL-17, and Th22/IL-22 positively regulated the occurrence of AD, while Th2/IL-4 and Treg/IL-35 negatively regulated the occurrence of AD. Plasma from AD patients further increased Bax mRNA levels but decreased Bcl2 and α-SMA mRNA levels in Ang II-treated HASMCs. Conclusions. Changes in Th1, Th2, Th9, Th17, Th22, and Treg activity are associated with the onset of AD. Different subsets of CD4+ T cells play different roles in the presence of AD.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely linked to heart failure and ...hypertension; however, its function in HEpEF resulting from salt-sensitive hypertension is not well understood. In this work, a salt-sensitive hypertension-induced HEpEF model was established based on deoxycorticosterone acetate-salt (DOCA-salt) hypertension mice. The impact of the MAPK inhibitor (Doramapimod) on HEpEF induced by salt-sensitive hypertension was assessed through various measures, such as blood pressure, transthoracic echocardiography, running distance, and histological analysis, to determine its therapeutic effectiveness on cardiac function. In addition, the effects of high salt on myogenic cells were also evaluated in vitro using qRTPCR. The LV ejection fractions (LVEF) in DOCA-salt hypertension mice were over 50%, indicating that the salt-sensitive hypertension-induced HFpEF model was successful. RNA-seq revealed that the MAPK signaling pathway was upregulated in the HFpEF model compared with the normal mice, accompanied by hypertension, impaired running distance, restricted cardiac function, increased cross-sectional and fibrosis area, and upregulation of heart failure biomarkers, including GAL-3, LDHA and BNP. The application of Doramapimod could improve blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis, as well as decrease the aforementioned heart failure biomarkers. The qRTPCR results showed similar findings to these observations. Our findings suggest that the use of a MAPK inhibitor (Doramapimod) could be a potential treatment for salt-sensitive hypertension-induced HFpEF.
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•DOCA-salt hypertension mice could be successfully applied to establish the heart failure preserved ejection fraction (HFpEF) model.•The MAPK signaling pathway is activated in HFpEF induced by salt-sensitive hypertension.•Application of a p38 MAPK inhibitor (Doramapimod) could improve blood pressure and heart function by suppressing the MAPK signaling pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Our previous study indicated that interleukin (IL)-37 is involved in atherosclerosis. In the present study, Anterior tibial arteries were collected from diabetes patients and controls. A ...histopathological analysis showed that IL-37 was over-expressed in human atherosclerotic plaques. Many types of cells including macrophages, vascular smooth muscle cells (VSMCs), endothelial cells and T lymphocyte expressed IL-37 in human atherosclerotic plaques. ApoE-/- mice were divided into a control group and a recombinant human IL-37-treated group. The IL-37 treatment resulted in a significant decrease in macrophages and CD4+ T lymphocytes and a substantial increase in VSMCs and collagen in atherosclerotic plaques, resulting in a reduction in atherosclerotic plaque size. Furthermore, the IL-37 treatment modulated the CD4+ T lymphocyte activity, including a decrease in T helper cell type 1 (Th1) and Th17 cells and an increase in regulatory T (Treg) cells, and inhibited the maturity of dendritic cells both in vivo and in vitro. In addition, treatment with anti-IL-10 receptor monoclonal antibody abrogated the anti-atherosclerotic effects of IL-37. These data suggest that exogenous IL-37 ameliorates atherosclerosis via inducing the Treg response. IL-37 may be a novel therapeutic to prevent and treat atherosclerotic disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Omentin-1, a novel adipocytokine mainly expressed in visceral adipose tissue, has been found to inhibit the inflammatory response and improve insulin resistance as well as other obesity-related ...disorders. This study investigated the association between omentin-1 expression in human epicardial adipose tissue (EAT) and coronary atherosclerosis.
Serum samples, and paired biopsies from EAT and subcutaneous adipose tissue (SAT), were obtained from patients with and without coronary artery disease (CAD, n = 28 and NCAD, n = 12, respectively) during elective cardiac surgery. Coronary angiography was performed to identify CAD presence. Serum omentin-1 and adiponectin levels were measured by ELISA. mRNA expression of omentin-1 and adiponectin was detected in adipose tissue by quantitative real-time PCR, and omentin-1 protein expression was evaluated by immunohistochemistry. Correlation and multivariate linear regression analyses were performed to determine the association between omentin-1 expression and clinical risk factors.
mRNA and protein expression of omentin-1 were higher in EAT than paired SAT in patients with CAD and NCAD. Compared with NCAD patients, CAD patients had lower omentin-1 and adiponectin mRNA levels in EAT and serum levels as well as lower omentin-1 protein levels. Among patients with CAD, omentin-1 expression was lower in EAT surrounding coronary segments with stenosis than those without stenosis, in terms of mRNA and protein, whereas adiponectin mRNA level in EAT did not seem to differ between stenotic and non-stenotic coronary segments in CAD patients. In multivariate linear regression analysis, CAD was an independent predictor of EAT omentin-1 mRNA expression (beta = -0.57, 95 % CI -0.89 to -0.24; P = 0.001) and serum omentin-1 levels (beta = -0.35, 95 % CI -0.67 to -0.03; P = 0.036).
Circulating and EAT-derived omentin-1 levels were reduced in patients with CAD. Omentin-1 expression in patients with CAD was lower in EAT adjacent to coronary stenotic segments than non-stenotic segments.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim: Several members of secreted frizzled-related protein (SFRP) are involved in the process of myocardial ischemia–reperfusion injury. However, little is known about the role of SFRP5 in patients ...with acute ST-segment elevation myocardial infarction (STEMI).Methods: In this cross-sectional study, 85 patients with first-time anterior STEMI who underwent timely primary percutaneous coronary intervention (PCI) and 35 patients without coronary artery disease (CAD) were enrolled. Serum SFRP5 levels were measured using an enzyme-linked immunosorbent assay kit. Patients with STEMI were divided into low-SFRP5 and high-SFRP5 groups according to their median baseline serum SFRP5 levels. To evaluate cardiac function and structure after infarction, the left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) were measured using echocardiography. The associations between changes in LVEF and reduced LVEF (≤ 50%) and clinical variables were determined by univariate and multivariate analyses.Results: Baseline serum SFRP5 levels were significantly higher in patients with STEMI than in those without CAD (23.3 ng/mL vs 19.8 ng/mL, P=0.008), although they decreased over time. Also, baseline serum SFRP5 levels were inversely correlated with peak hypersensitive cardiac troponin I (hs-cTnI) levels (r=−0.234, P=0.025) and peak hypersensitive C-reactive protein (hs-CRP) levels (r=−0.262, P=0.015). A multivariate linear regression model showed that changes in LVEF were positively correlated with serum SFRP5 levels at baseline (β= 0.249, 95% confidence interval (CI) 0.018–0.245, P=0.024) and 24 h after admission (β=0.220, 95% CI 0.003–0.264, P=0.045). At 3 months, LVEF in patients with high SFRP5 levels was significantly improved over baseline (60.8±7.1) % vs (56.1±7.5) %, P=0.001. LVEF was also significantly higher in patients with high SFRP5 levels than in those with low at the 3-month follow-up (60.8±7.1) % vs (56.8±8.9) %, P=0.028. Consequently, high serum SFRP5 levels at baseline were associated with a decreased risk of reduced LVEF at 3 months, independent of peak hs-cTnI and baseline cardiac function (hazard ratio 0.190, 95% CI 0.036–0.996; P=0.049).Conclusions: High serum SFRP5 levels measured during the acute phase of STEMI were significantly associated with promoting myocardial recovery at an early phase following primary PCI, suggesting that SFRP5 is a potential therapeutic target in acute STEMI.
Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial ...influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown.
The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms.
We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM.
Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Accumulating evidence shows that the novel anti-inflammatory cytokine IL-35 can efficiently suppress effector T cell activity and alter the progression of inflammatory and autoimmune diseases. The ...two subunits of IL-35, EBI3 and p35, are strongly expressed in human advanced plaque, suggesting a potential role of IL-35 in atherosclerosis and coronary artery disease (CAD). However, the plasma levels of IL-35 in patients with CAD have yet to be investigated.
Plasma IL-35, IL-10, TGF-β1, IL-12 and IL-27 levels were measured using an ELISA in 43 stable angina pectoris (SAP) patients, 62 unstable angina pectoris (UAP) patients, 56 acute myocardial infarction (AMI) patients and 47 chest pain syndrome patients as a control group.
The results showed that plasma IL-35 levels were significantly decreased in the SAP group (90.74±34.22 pg/ml), the UAP group (72.20±26.63 pg/ml), and the AMI group (50.21±24.69 pg/ml) compared with chest pain syndrome group (115.06±32.27 pg/ml). Similar results were also demonstrated with IL-10 and TGF-β1. Plasma IL-12 and IL-27 levels were significantly increased in the UAP group (349.72±85.22 pg/ml, 101.75±51.42 pg/ml, respectively) and the AMI group (318.05±86.82 pg/ml, 148.88±68.45 pg/ml, respectively) compared with chest pain syndrome group (138.68±34.37 pg/ml, 63.60±22.75 pg/ml, respectively) and the SAP group (153.84±53.86 pg/ml, 70.84±38.77 pg/ml, respectively). Furthermore, lower IL-35 levels were moderately positively correlated with left ventricular ejection fraction (LVEF) in CAD patients (R = 0.416, P<0.01), whereas higher IL-27 levels were weakly negatively correlated with LVEF in CAD patients(R = -0.205, P<0.01).
The results of the present study show that circulating IL-35 is a potentially novel biomarker for coronary artery disease. Regulating the expression of IL-35 also provides a new possible target for the treatment of atherosclerosis and CAD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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