Qiu Jing Chen

MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4.

Atherosclerosis is an inflammatory process due to oxidized low‐density lipoprotein (oxLDL) accumulation in macrophages. We investigated the involvement of microRNAs in oxLDL accumulation and inflammatory response in macrophages. The expression of miR‐146a decreases under oxLDL stimulation. MiR‐146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C–C motif) ligand 2 and matrix metallopeptidase 9. Toll‐like receptor 4 (TLR4) is a relevant target of miR‐146a, and miR‐146a inhibits the activation of TLR4‐dependent intracellular signaling pathways involved in cytoskeleton rearrangement, lipid uptake, and inflammatory cytokine secretion. These results indicate that miR‐146a contributes to the regulation of both oxLDL accumulation and inflammatory response by negatively regulating TLR4 and thereby inhibiting the activation of TLR4‐dependent signaling pathways. Over‐expression of miR‐146a may be useful in the prevention and treatment of atherosclerosis.

Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients

OBJECTIVE This cross-sectional study tested the hypothesis that increased serum level of high mobility group box-1 protein (HMGB1), a pro-inflammatory ligand of receptor for advanced glycation end products (RAGE), is associated with coronary artery disease (CAD) in nondiabetic and type 2 diabetic patients. METHODS Serum levels of HMGB1, endogenous secretory RAGE (esRAGE), soluble RAGE (sRAGE) and inflammatory cytokines were determined in 512 patients categorized as Group I (n=132, without diabetes and CAD), Group II (n=149, with CAD but no diabetes), Group III (n=80, with diabetes but no CAD) and Group IV (n=151, with diabetes and CAD). RESULTS Serum levels of HMGB1 and hsCRP were higher in Group II than in Group I, and in Group IV than in Group III (all P<0.001). HMGB1 was positively related to hsCRP, TNF-alpha and IL-6 levels in the whole subjects (all P<0.01). Group II patients had lower sRAGE (P=0.058) and esRAGE (P<0.001) levels versus those in Group I. However, in the diabetic patients, those in Group IV had lower esRAGE (P<0.001) but higher sRAGE (P=0.002) levels compared to those in Group III. In multivariable regression analysis, HMGB1, esRAGE and conventional risk factors (age, smoking, hypertension, HDL-C, hsCRP, TNF-alpha) were independent determinants of CAD in nondiabetic patients. Moreover, HMGB1 and esRAGE consistently remained to be independently associated with CAD in diabetic patients, so did other major conventional risk factors. CONCLUSION This study demonstrates that increased serum HMGB1 level is associated with CAD in nondiabetic and type 2 diabetic patients.

Increased glycated albumin and decreased esRAGE levels are related to angiographic severity and extent of coronary artery disease in patients with type 2 diabetes

OBJECTIVE This cross-sectional study aimed at evaluating the possible association of serum levels of glycated albumin (GA) and endogenous secretory RAGE (esRAGE) with angiographically significant coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) and non-diabetic patients. METHODS Serum levels of GA, esRAGE, and inflammatory markers were measured in 1320 patients undergoing coronary angiography from three large districts in Shanghai. Patients were divided into four groups based on the presence/absence of T2DM and of significant CAD (diameter stenosis >or=70%). RESULTS Serum levels of GA, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were significantly higher and, in contrast, serum esRAGE levels were lower in patients with both T2DM and significant CAD than in all other groups (all P<0.01), whereas there were no significant differences in GA and esRAGE levels between non-diabetic patients with CAD and those without. Serum GA and esRAGE levels correlated with angiographic CAD severity (P=0.031 and P=0.001), extent (both P<0.001) and number of diseased coronary arteries (both P<0.001) in diabetic CAD patients. At multivariable regression analysis, male gender, age, hypertension, cigarette smoking, HDL-C, lipoprotein (a), GA, esRAGE, hsCRP and TNF-alpha were all independent determinants of significant CAD in diabetic patients. Moreover, male gender, age, hypertension, lipoprotein (a), GA and esRAGE remained independently associated with three-vessel disease. CONCLUSION Patients with T2DM and CAD feature elevated serum GA and decreased serum esRAGE levels. Here serum GA and esRAGE levels are associated with angiographic extent and severity of CAD.

Increased serum high-mobility group box-1 and cleaved receptor for advanced glycation endproducts levels and decreased endogenous secretory receptor for advanced glycation endproducts levels in diabetic and non-diabetic patients with heart failure

High‐mobility group box‐1 (HMGB1) is a ligand for the receptor for advanced glycation endproducts (RAGE). An HMGB1–RAGE interaction has been implicated in cardiac dysfunction. We assessed the association of HMGB1 and RAGE isoforms with heart failure (HF) in diabetic and non‐diabetic patients.

Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells.

BackgroundAdvanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs). MSCs have a potential role in cell replacement therapy in acute myocardial infarction and ischemic cardiomyopathy. However, mechanisms of AGEs on MSCs are still not unveiled.MethodsReactive oxygen species (ROS), genes regulation, cell proliferation and migration have been detected by AGE-BSA stimulated MSCs.ResultsWe found that in vitro stimulation with AGE-BSA induced generation of reactive oxygen species (ROS), and inhibited dose-dependently proliferation and migration of MSCs. Microarray and molecular biological assessment displayed an increased expression and secretion of Ccl2, Ccl3, Ccl4 and Il1b in a dose- and time-dependent manner. These chemokines/cytokines of equivalent concentration to those in conditioned medium exerted an inhibitory effect on MSC proliferation and migration after stimulation for 24 h. Transient elevation of phospho-p38 in MSCs upon AGE-BSA stimulation was blocked with p38 inhibitor.ConclusionsThe study indicates that AGE-BSA induces production of chemokines/cytokines in a dose- and time-dependent manner via activation of ROS-p38 mediated pathway. These chemokines/cytokines exert an inhibitory effect on MSC growth and migration, suggesting an amplified dysfunction of MSCs by AGEs.

Association of increased S100B, S100A6 and S100P in serum levels with acute coronary syndrome and also with the severity of myocardial infarction in cardiac tissue of rat models with ischemia–reperfusion injury

OBJECTIVE We aim to check if serum levels of receptor for advanced glycation endproduct (RAGE) ligands S100B, S100A6 and S100P were related to myocardial injury in acute coronary syndrome (ACS). METHODS Serum levels of S100B, S100A6, S100P, and soluble RAGE (sRAGE) were analyzed in 882 patients. Based upon clinical and laboratory findings, they were assigned into control (n=251), stable angina (n=211), and ACS (n=420). To verify clinical data of ACS, forty Sprague-Dawley rats were subjected to cardiac ischemia-reperfusion (I/R) injury by occluding proximal (large infarct size; n=20) or distal (small infarct size; n=20) left anterior descending coronary artery, and another 20 rats were in sham-operation group. The expressions of S100B, S100A6, S100P and RAGE in the myocardium were analyzed. RESULTS Serum levels of S100B, S100A6 and S100P were higher in ACS group than in stable angina and control groups, and sRAGE levels were higher in ACS patients versus controls (all p<0.01). S100B and S100P levels correlated significantly with CK-MB and troponin I levels in ACS group (all p<0.05). In multivariable regression analysis, S100B, S100A6, S100P and conventional risk factors were independently associated with ACS. In animal models, the expressions of S100B, S100A6 and S100P were closely related to infarct size (all p<0.05). CONCLUSION This study indicates that serum levels of S100B, S100A6 and S100P are associated with ACS, and serum levels and myocardial expression of these proteins are related to infarct size.

RAGE Gene Polymorphisms Are Associated with Circulating Levels of Endogenous Secretory RAGE but Not with Coronary Artery Disease in Chinese Patients with Type 2 Diabetes Mellitus

BACKGROUND AND AIMS Engagement of the receptor for advanced glycation end products (RAGE) with advanced glycation end products and subsequent signaling play an important role in the development of diabetic complications. This pathophysiological effect was mitigated partially by endogenous secretory RAGE (esRAGE). The present study aimed to explore the possible association of RAGE polymorphism with serum esRAGE level and coronary artery disease (CAD) in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS A total of 740 consecutive patients with T2DM undergoing coronary angiography were enrolled. The severity of coronary atherosclerosis was defined as the number of diseased vessels; 69 bp insertion/deletion was determined by polymerase chain reactions, and -429 T/C, -374A/T and G82S variants were assessed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS Patients with genotypes carrying C allele of -429 T/C and G allele of G82S had significantly higher esRAGE levels. 82S allele was also associated with increased tumor necrosis factor-alpha and interleukin-6 levels in diabetic patients with CAD (all p <0.05), but none of the polymorphisms or haplotypes was related to the presence and severity of CAD. CONCLUSIONS G82S and -429 T/C polymorphisms of RAGE were associated with the circulating levels of esRAGE but not with CAD in Chinese patients with T2DM.

Association of serum glycated albumin, C-reactive protein and ICAM-1 levels with diffuse coronary artery disease in patients with type 2 diabetes mellitus

BACKGROUND We assessed the possible association of glycated albumin (GA) and circulatory adhesion molecules with diffuse coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). METHODS Six hundred and two consecutive patients with CAD, based upon angiographic features and presence or absence of T2DM, were categorized as Group I (296 patients with non-diffuse CAD but no T2DM), Group II (138 patients with diffuse CAD but no T2DM), Group III (78 patients with non-diffuse CAD and T2DM) and Group IV (90 patients with diffuse CAD and T2DM). Serum levels of glycated albumin, adhesion molecules, endogenous secretory receptor of advanced glycation end products (esRAGE) and inflammatory factors were determined. RESULTS Serum levels of GA, hsCRP, sVCAM-1, sICAM-1 and sE-selectin were increased, while esRAGE levels were decreased in diabetic patients than in non-diabetic patients (all P<0.001). These levels (except sVCAM-1 and sE-selectin) differed between Groups III and IV (all P<0.05). Moreover, GA levels correlated with sE-selectin and sICAM-1 concentrations (both P<0.05). Multivariable regression analysis revealed that male, hypertension, GA, hsCRP and sICAM-1 were independently associated with diffuse CAD in diabetic patients. CONCLUSIONS This study addresses an association of increased GA, hsCRP and sICAM-1 levels with diffuse CAD in patients with T2DM.

Increased glycated albumin and decreased esRAGE concentrations are associated with in-stent restenosis in Chinese diabetic patients.

BACKGROUND We investigated the impact of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) and RAGE polymorphisms on occurrence of in-stent restenosis (ISR) in Chinese patients with type 2 diabetes. METHODS Four hundred nineteen patients with diabetes were divided, based upon the presence or absence of coronary artery disease (CAD) and ISR, into Group I (205 patients without CAD), Group II (128 patients with CAD but without ISR) and Group III (86 patients with ISR). One hundred fifty-two normal subjects were served as controls. Serum concentrations of GA and esRAGE were measured, and RAGE polymorphisms (-374T>A, -429T>C and G82S) were analyzed. RESULTS Serum GA concentration was higher and, in contrast, esRAGE concentration was lower in Group III than in the other groups (P<0.05). These two protein concentrations correlated closely with loss index (all P<0.01), and were independent risk factors for ISR in diabetic patients (P=0.01 and P=0.025, respectively). However, there were no differences in the allele and genotype frequencies in the 3 polymorphisms of RAGE gene between groups. CONCLUSIONS Increased GA and decreased esRAGE concentrations, but not -374T>A, -429T>C and Gly82Ser polymorphisms of RAGE gene, are associated with ISR in Chinese patients with type 2 diabetes.

C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis

AIMS We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 μg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice.