High-mobility group box 1 and its related receptors: potential therapeutic targets for contrast-induced acute kidney injury.

Percutaneous coronary intervention (PCI) is a crucial diagnostic and therapeutic approach for coronary heart disease. Contrast agents' exposure during PCI is associated with a risk of contrast-induced acute kidney injury (CI-AKI). CI-AKI is characterized by a sudden decline in renal function occurring as a result of exposure to intravascular contrast agents, which is associated with an increased risk of poor prognosis. The pathophysiological mechanisms underlying CI-AKI involve renal medullary hypoxia, direct cytotoxic effects, endoplasmic reticulum stress, inflammation, oxidative stress, and apoptosis. To date, there is no effective therapy for CI-AKI. High-mobility group box 1 (HMGB1), as a damage-associated molecular pattern molecule, is released extracellularly by damaged cells or activated immune cells and binds to related receptors, including toll-like receptors and receptor for advanced glycation end product. In renal injury, HMGB1 is expressed in renal tubular epithelial cells, macrophages, endothelial cells, and glomerular cells, involved in the pathogenesis of various kidney diseases by activating its receptors. Therefore, this review provides a theoretical basis for HMGB1 as a therapeutic intervention target for CI-AKI.

YTHDC2-Mediated circYTHDC2 N6-Methyladenosine Modification Promotes Vascular Smooth Muscle Cells Dysfunction Through Inhibiting Ten-Eleven Translocation 2.

Type 2 diabetes condition mediated vascular smooth muscle cell (VSMCs) dysfunction. However, the mechanism of VSMCs dysfunction in diabetic patients needs further elucidation. VSMCs are an important component of the vascular wall, participate in the process of vascular remodeling, and play a vital role in the vascular complications of diabetes. Studies have found that circular RNAs (circRNAs) play a key regulatory role in the occurrence and development of VSMCs dysfunction. In this study, we stimulated VSMCs with high glucose and identified a new circular RNA, circYTHDC2, using circRNA chip analysis. circYTHDC2 was highly expressed in VSMCs treated with high glucose. Knockout of circYTHDC2 significantly inhibited the proliferation and migration of VSMCs. Metformin treatment significantly inhibited the expression of YTHDC2 and circYTHDC2. The upstream mechanism analysis revealed that the stability of circYTHDC2 was regulated by YTHDC2-mediated m6A modification. Furthermore, circYTHDC2 negatively regulates the expression of Ten-Eleven Translocation 2 (TET2) by targeting the unstable motif of TET2 3'UTR, thereby promoting dedifferentiated "synthetic type" transformation of VSMC. Taken together, these results suggest that the YTHDC2/circYTHDC2/TET2 pathway is an important target of metformin in preventing the progression of VSMCs dysfunction under high glucose.

ADAMTS-5 Decreases in Aortas and Plasma From Aortic Dissection Patients and Alleviates Angiotensin II-Induced Smooth Muscle-Cell Apoptosis.

Background: Acute aortic dissection (AAD) is associated with degeneration of the aortic media and accompanied by vascular extracellular matrix (ECM) remodeling. Recently, a disintegrin and metalloproteinase with thrombospondin type 1 motifs-5 (ADAMTS-5) has been reported to be involved in ECM remodeling and vascular diseases. The aim of this study was to examine ADAMTS-5 levels in AAD patients and investigate the underlying mechanisms. Methods: Aortic tissue samples were collected from normal donors and AAD patients, and the expression of ADAMTS-5 was analyzed in all aortic tissues. In addition, plasma levels of ADAMTS-5, matrix metalloproteinase (MMP)-2 and MMP-9, and tumor necrosis factor-α (TNF-α) were measured in repeated samples from AAD patients and compared to the non-AAD (NAD) group. In addition, we investigated the effects of ADAMTS-5 in smooth muscle cell (SMC) apoptosis. Results: The results showed that ADAMTS-5 expression was significantly reduced in the aortas of AAD patients and that SMCs were the main source of ADAMTS-5. In addition, the plasma ADAMTS-5 level was lower, but plasma MMP-2, MMP-9, and TNF-α levels were increased in the AAD patients. Multivariate linear regression analyses showed that a decreased ADAMTS-5 level in patients was independently associated with an increased risk of AAD. Furthermore, recombinant human ADAMTS-5 significantly ameliorated angiotensin (Ang II)-evoked SMC apoptosis. Conclusions: ADAMTS-5 shows promise as a novel potential biomarker for AAD, and regulation of SMC is a possible mechanism for the effects of ADAMTS-5.

IL-22 produced by Th22 cells aggravates atherosclerosis development in ApoE-/- mice by enhancing DC-induced Th17 cell proliferation.

Th22 cells are a novel subset of CD4+ T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE-/- mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4+ cells, play a major role in atherosclerosis. ApoE-/- mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3+ T cells, CD68+ macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti-IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4+ T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.

Circular RNA_101237 mediates anoxia/reoxygenation injury by targeting let­7a­5p/IGF2BP3 in cardiomyocytes.

Circular RNAs (circRNAs) serve important roles in cardiovascular diseases, including myocardial infarction. However, the mechanisms underlying the roles of circRNAs in cardiomyocyte death induced by anoxia/reoxygenation (A/R) are not fully understood. In the present study, the roles of circRNA_101237 and let­7a­5p in cardiomyocyte death induced by A/R injury were investigated. It was identified that circRNA_101237 was induced by A/R injury in a time­dependent manner and that circRNA_101237 knockdown protected cardiomyocytes from A/R­mediated apoptosis. Additional mechanistic studies revealed that circRNA_101237 served as a sponge for let­7a­5p, subsequently regulating insulin­like growth factor 2 mRNA­binding protein 3 (IGF2BP3)­dependent autophagy. IGF2BP3 downregulation decreased the levels of apoptosis and inhibited autophagy induced by A/R challenge in primary cardiomyocytes. These results identified circRNA_101237 as a novel circRNA that regulates cardiomyocyte death and autophagy, and demonstrated that the circRNA­101237/let­7a­5p/IGF2BP3 axis, which serves as a regulator of cardiomyocyte death, may be a potential therapeutic target for the management of cardiovascular diseases.

Thrombospondin 1 Is Increased in the Aorta and Plasma of Patients With Acute Aortic Dissection.

BACKGROUND: Previous studies have shown that thrombospondin 1 (TSP-1) is involved in cardiovascular diseases, such as atherosclerosis and abdominal aortic aneurysm. However, TSP-1 expression levels in human aortic dissection (AD) remain unknown. METHODS: TSP-1 levels were detected in aortas collected from control subjects and AD patients. The TSP-1, interleukin (IL) 6, matrix metalloproteinase (MMP) 2, and MMP9 levels in plasma from non-AD patients and AD patients were measured. In addition, the effects of recombinant mouse TSP-1 protein on macrophage differentiation and smooth muscle cell (SMC) apoptosis were investigated. RESULTS: Compared with the aortas from control subjects, aortas from AD patients showed a significant increase in TSP-1 expression, especially in the torn sections. SMCs and endothelial cells produced TSP-1, but SMCs were the main source. TSP-1, IL-6, MMP2, and MMP9 levels were higher in AD patients than in non-AD patients, and plasma IL-6, MMP2, and MMP9 levels were positively correlated with TSP-1 levels in AD patients. Simple linear regression analysis and multivariate linear regression analysis showed that TSP-1 levels were independently correlated with the onset of AD. In cultured cells, recombinant mouse TSP-1 further increased inducible nitric oxide synthase (iNOS) mRNA expression in angiotensin (Ang) II-treated macrophages, whereas it reduced B-cell lymphoma-2 (Bcl2) mRNA levels and increased Bcl2-associated X protein (Bax) mRNA levels in Ang II-treated SMCs. CONCLUSIONS: TSP-1 level is significantly increased in AD patients and might participate in AD via promoting classically activated macrophage (M1) macrophage differentiation and SMC apoptosis.

Cytokines in aortic dissection.

Aortic dissection (AD) is one of the most dangerous forms of vascular disease, characterized by endometrial rupture and intramural hematoma formation. Generally, the pathological process is complicated and closely related to the infiltration of inflammatory cells into the aortic wall and apoptosis of vascular smooth muscle cells. Currently, multiple cytokines, including interleukins, interferon, the tumor necrosis factor superfamily, colony stimulating factor, chemotactic factor, growth factor and so on, have all been demonstrated to play a critical role in AD. Additionally, studies of the link between cytokines and AD could deepen our understanding of the disease and may guide future treatment therapies; therefore, this review focuses on the role of cytokines in AD.

[Association between ABO blood groups and coronary heart disease in Chinese Guangxi Zhuang population].

OBJECTIVE: To investigate this association between ABO blood groups and coronary heart disease (CHD) in the Chinese Guangxi Zhuang population. METHODS: From August 2010 to April 2013, we performed a case-control study in a Chinese Zhuang population, which included 1 024 CHD cases and 1 024 age and gender-matched non-CHD controls. The ABO blood groups and biological variables were measured by standard laboratory procedures. The Gensini score was used to evaluate the severity of coronary artery stenosis. RESULTS: Compared to non-CHD control group, CHD group had higher levels of fasting blood glucose ((6.71 ± 6.72) mmol/L vs. (4.98 ± 1.55) mmol/L, P < 0.001), LDL-C ((2.89 ± 1.18) mmol/L vs. (2.60 ± 1.05) mmol/L, P = 0.002) and CRP ((7.74 ± 7.32) mg/L vs. (2.93 ± 2.19)mg/L, P < 0.001) as well as higher proportion of history of hypertension (57.0% vs. 27.5%, P < 0.001), history of diabetes (29.6% vs. 9.6%, P < 0.001), family history of CHD (35.3% vs. 10.6%, P < 0.001) and smoking (51.0% vs. 38.2%, P < 0.001). Logistic analysis indicated that ABO blood groups were associated with CHD risk in the Chinese Zhuang population. Compared with group O, the group B individuals had a higher risk of CHD (OR = 2.33, 95% CI 1.88-2.90, P < 0.001), this result remained after adjustment for the conventional CHD risk factors (OR = 1.55, 95% CI 1.05-2.52, P = 0.047). In addition, there were significant differences of Gensini score between non-O subjects and group O subjects in the CHD group, and MACE at 1-year follow-up was similar between ABO blood groups of CHD individuals. CONCLUSION: ABO blood groups are associated with CHD risk in the Chinese Zhuang population.

Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome.

OBJECTIVE: More recently, evidence showed that the novel anti-inflammatory cytokine interleukin- (IL-) 37 was expressed in the foam-like cells of atherosclerotic coronary and carotid artery plaques, suggesting that IL-37 is involved in atherosclerosis-related diseases. However, the plasma levels of IL-37 in patients with acute coronary syndrome (ACS, including unstable angina pectoris and acute myocardial infarction) have yet to be investigated. METHODS: Plasma IL-37, IL-18, and IL-18BP levels were measured in 50 patients with stable angina pectoris (SAP), 75 patients with unstable angina pectoris (UAP), 67 patients with acute myocardial infarction (AMI), and 65 control patients. RESULTS: The plasma IL-37, IL-18, and IL-18BP levels were significantly increased in ACS patients compared to SAP and control patients. A correlation analysis showed that the plasma biomarker levels were positively correlated with each other and with the levels of C-reactive protein (CRP), N-terminal probrain natriuretic peptide (NT-proBNP), and left ventricular end-diastolic dimension (LVEDD) but negatively correlated with left ventricular ejection fraction (LVEF). Furthermore, the plasma IL-37, IL-18, and IL-18BP had no correlation with the severity of the coronary artery stenosis. CONCLUSIONS: The results indicate that the plasma IL-37 levels are associated with the onset of ACS.

Circulating Th22 and Th9 levels in patients with acute coronary syndrome.

BACKGROUND: CD4+ T helper (Th) cells play critical roles in the development and progression of atherosclerosis and the onset of acute coronary syndromes (ACS, including acute myocardial infarction (AMI) and unstable angina pectoris (UAP)). In addition to Th1, Th2, and Th17 cells, Th22 and Th9 subsets have been identified in humans. In the present study, we investigated whether Th22 cells and Th9 cells are involved in the onset of ACS. METHODS: The frequencies of Th22 and Th9 cells were detected using a flow cytometric analysis and their related cytokine and transcription factor were measured in the AMI, UAP, stable angina pectoris (SAP), and control groups. RESULTS: The results revealed a significant increase in the peripheral Th22 number, AHR expression, and IL-22 levels in patients with ACS compared with those in the SAP and control groups. Although there was no difference in the peripheral Th9 number among the four groups, the PU.1 expression and IL-9 levels were significantly increased in patients with ACS compared with the SAP and control groups. CONCLUSIONS: Circulating Th22 and Th9 type responses may play a potential role in the onset of ACS symptom.

Downregulation of CD4+LAP+ and CD4+CD25+ regulatory T cells in acute coronary syndromes.

BACKGROUND: Regulatory T (Treg) cells play a protective role in atherosclerosis prone models and are related to the onset of acute coronary syndromes (ACS, including non-ST-elevation ACS (NSTEACS) and ST-elevation acute myocardial infarction (STEAMI)). CD4+LAP+ Treg cells are a novel subset of Tregs that have been found to ameliorate atherosclerosis in ApoE(-/-) mice, and these cells also exist in humans. The present study was designed to investigate whether CD4+LAP+ Treg cells are involved in the onset of ACS. METHODS: The frequencies of CD4+LAP+ and CD4+CD25+ Treg cells were detected using flow cytometric analysis, and the plasma IL-10 and TGF- ß 1 levels were measured using an ELISA in 29 stable angina (SA) patients, 30 NSTEACS patients, 27 STEAMI patients, and a control group (30 cases). RESULTS: The results revealed a significant decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells and in the levels of IL-10 and TGF- ß 1 in patients with ACS compared with those in the SA and control groups. CONCLUSIONS: The decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells may play a role in the onset of ACS.

Decreased plasma IL-35 levels are related to the left ventricular ejection fraction in coronary artery diseases.

BACKGROUND: 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. METHODS: Plasma IL-35, IL-10, TGF-ß1, 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. RESULTS: 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-ß1. 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). CONCLUSIONS: 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.

High-precision system for automatic null ellipsometric measurement.

A system for automatic null ellipsometric measurement, which uses a new kind of achromatic rhomb-type lambda/4 retarder, is designed and constructed. By use of terbium glass as the modulator's material, a magneto-optical modulator and its driving circuit are constructed. The polarized light is modulated by dc and ac. Combined with an ultra-low noise frequency-selective amplifier and a lock-in amplifier, the null time of the mechanical and photoelectric automatic null system can be less than 15 s. After the error of the mechanical parts is excluded, the repeatability standard deviation S4 of nulling angles can be less than 0.00025 deg.