Ming Zhong

Increased serum visfatin in patients with metabolic syndrome and carotid atherosclerosis

Objectiveu2003 Visfatin is a newly identified adipocytokine and recent studies indicated that visfatin may have potential proinflammatory effect. However, its pathophysiological role in the metabolic syndrome (MetS) is not fully understood. In this study we investigated whether serum visfatin levels is altered in patients with the MetS, and compared the levels of visfatin between patients with and without carotid plaques.

Differential regulation of collagen types I and III expression in cardiac fibroblasts by AGEs through TRB3/MAPK signaling pathway

Abstract.Advanced glycation end products (AGEs) play an important role in collagen deposition in diabetic cardiomyopathy. TRB3, a mammalian homolog of Drosophila tribbles, functions to increase glucose intolerance and regulates cell proliferation. We demonstrated that AGEs induce collagen type I expression but inhibit collagen type III expression, accompanied by increased TRB3 expression. Furthermore, the collagen type I induced byAGEs was down-regulated after inhibition of ERK and p38-MAPK, the collagen type III reduced by AGEs was up-regulated after inhibition of ERK. The expression of collagen types I and III regulated by AGEs through MAPK was partly reversed after treatment with TRB3 siRNA. It suggests that the TRB3/MAPK signaling pathway participates in the regulation of collagen types I and III by AGEs and may provide new therapeutic strategies for diabetic cardiomyopathy.

β1 Adrenergic Receptor Polymorphisms and Heart Failure: A Meta-Analysis on Susceptibility, Response to β-Blocker Therapy and Prognosis

Aims The risk stratification of patients for heart failure (HF) remains a challenge, as well as the anticipation of the response to β-blocker therapy. Since the pivotal role of β1 adrenergic receptor (β1-AR) in HF, many publications have studied the associations between the β1-AR polymorphisms (Ser49Gly and Arg389Gly) and HF, with inconsistent results. Thus, we performed a meta-analysis of studies to evaluate the impact of β1-AR polymorphisms on susceptibility to HF, the response to β-blocker therapy and the prognosis of HF. Methods and Results Electronic databases were systematically searched before August 2011. We extracted data sets and performed meta-analysis with standardized methods. A total of 27 studies met our inclusion criteria. It was found that in East Asians, the Gly389 allele and Gly389 homozygotes significantly increased the HF risk, while the Gly389 allele and Gly389 homozygotes trended to decrease the risk of HF in whites. With the similar reduction of heart rate, overall, the Arg389 homozygotes showed a better response to β-blocker therapy. Furthermore, the Arg389 homozygotes were significantly associated with better LVEF improvement in East Asians and a mixed population. And in white people, the Arg389 homozygotes made a greater LVESd/v improvement and trended to be associated with better LVEDd/v improvement. However, the prognosis of Arg389 homozygotes HF patients was similar to those with Gly389 carriers. The Ser49Gly polymorphism did not impact the risk or prognosis of HF. Conclusion Based on our meta-analysis, the Gly389 allele and Gly389 homozygotes were risk factors in East Asians while trending to protect whites against HF. Furthermore, Arg389 homozygote is significantly associated with a favorable response to β-blocker treatment in HF patients. However, neither of the two polymorphisms is an independent predictor of the prognosis of HF.

IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome.

Although considerable evidence implicates the cytokine interlukin-18 (IL-18) in metabolic syndrome (MetS), the direct effect of IL-18 on vascular changes of MetS remains unknown. We investigated the chronic in vivo effect of IL-18 on development of MetS and vascular inflammation and remodeling by overexpressing IL-18 protein in fructose-fed rats (FFR), a model of MetS using intravenous administration of an adenovirus encoding rat IL-18. Increased serum IL-18 and vascular inflammatory response were found in FFR. Overexpression of IL-18 aggravated insulin resistance and enhance vascular inflammation and remodeling, which can be reflected by increased aortic expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and enhanced infiltration of macrophages and increased aortic wall thickness and wall-to-lumen ratio. Interestingly, the levels of interleukin-1 receptor-associated kinase 1 (IRAK1) and the activity of nucleus factor-kappaB (NF-kappaB) were also significantly increased. Together, these results indicated that chronic elevated IL-18 levels at a supraphsiological concentration aggravated insulin resistance, enhanced vascular inflammation and remodeling, probably by increasing the level of IRAK1 and the activity of NF-kappaB. Targeting expression of IL-18 or its specific downstream mediators may retard the progression of MetS and its complications.

Felodipine attenuates vascular inflammation in a fructose-induced rat model of metabolic syndrome via the inhibition of NF-κB activation

AbstractAim:Metabolic syndrome is associated with an increased incidence of atherosclerosis. Clinical studies have shown that calcium channel blockers (CCB) inhibit the progression of atherosclerosis. However, the underlying mechanism is unclear. We investigated the inhibitory effect of felodipine on adhesion molecular expression and macrophage infiltration in the aorta of high fructose-fed rats (FFR).Methods:Male Wistar rats were given 10% fructose in drinking water. After 32 weeks of high fructose feeding, they were treated with felodipine (5 mg·kg-1·d-1) for 6 weeks. The control rats were given a normal diet and water. The aortic expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the infiltration of macrophages were measured by real-time RT-PCR and/or immunohistochemistry. NF-κB activity was measured by electrophoretic mobility shift assay (EMSA).Results:After 32 weeks of high fructose feeding, FFR displayed increased body weight, systolic blood pressure (SBP), serum insulin, and triglycerides when compared with the control rats. The aortic expressions of ICAM-1 and VCAM-1 were significantly increased in FFR than in the control rats and accompanied by the increased activity of NF-κB. FFR also showed significantly increased CD68-positive macrophages in the aortic wall. After treatment with felodipine, SBP, serum insulin, and the homeostasis model assessment decreased significantly. In addition to reducing ICAM-1 and VCAM-1, felodipine decreased macrophages in the aortic wall. EMSA revealed that felodipine inhibited NF-κB activation in FFR.Conclusion:Felodipine inhibited vessel wall inflammation. The inhibition of NF-κB may be involved in the modulation of vascular inflammatory response by CCB in metabolic syndrome.

Changes in connexin 43, metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy in dogs

To study changes in connexin, metalloproteinase and tissue inhibitor of metalloproteinase levels during tachycardia‐induced cardiomyopathy (TIC).

The role of thrombospondin-1-mediated TGF-β1 on collagen type III synthesis induced by high glucose

Transforming growth factor-β1 (TGF-β1) has been thought to play a major role during cardiac fibrosis in the development of diabetic cardiomyopathy, and cardiac fibrosis mainly as a result of an increase of collagen type III occurs in the human hearts with diabetes. Thrombospondin-1 (TSP-1) has been reported to activate the latent complex of TGF-β1. We examined the effects of TSP-1 on the expression of TGF-β1 and collagen type III by rat cardiac fibroblasts in high ambient glucose. We demonstrated that high glucose induces the mRNA and protein expression of collagen type III, TGF-β1, and TSP-1. Furthermore, the mRNA and protein expression of collagen type III induced by high glucose was downregulated after treatment with TGF-β1 antibody, or TSP-1 siRNA. The expression of TGF-β1 increased by high glucose was also reversed after treatment with TSP-1 siRNA. Our findings suggest that the TSP-1 participates in the upregulation of TGF-β1, collagen type III by high glucose and may provide new therapeutic strategies for diabetic cardiomyopathy.

Activin receptor-like kinase 7 mediates high glucose-induced H9c2 cardiomyoblast apoptosis through activation of Smad2/3

Cardiomyocyte apoptosis is an important pathological change of diabetic cardiomyopathy. How the elevated glucose levels cause cell apoptosis remains unknown. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 signaling pathway plays an important role in high glucose-induced cardiomyocyte apoptosis. H9c2 cardiomyoblasts and neonatal rat cardiomyocytes were treated with 33mmol/l glucose. The expression of ALK7, Smad2 and Smad3 were inhibited by small interfering RNA respectively. The level of ALK7, total Smad2/3, phosphorylated Smad2/3, B-cell lymphoma-2 (Bcl-2) and cleaved Caspase3 were evaluated using western blot. The apoptosis rate was detected by flow cytometer. High glucose treatment caused the apoptosis of H9c2 cardiomyocyte and the inhibition of Smad2 or Smad3 attenuated this apoptosis. ALK7 existed in both H9c2 cardiomyoblasts and neonatal rat cardiomyocytes and high ambient glucose upregulated its expression. The increased expression level of cleaved Caspase3 and apoptosis rate and decreased expression of Bcl-2 were reversed after ALK7 was inhibited. The expression of phosphorylated Smad2/3 also decreased after the knockdown of ALK7. Our findings suggest that ALK7 mediates high ambient glucose-induced H9c2 cardiomyoblasts apoptosis through the activation of Smad2/3.

Overexpressing STAMP2 Improves Insulin Resistance in Diabetic ApoE−/−/LDLR−/− Mice via Macrophage Polarization Shift in Adipose Tissues

STAMP2 is a counterregulator of inflammation and insulin resistance. The aim of this study is to investigate whether activation of STAMP2 improves insulin resistance by regulating macrophage polarization in adipose tissues. The diabetic ApoE−/−/LDLR−/− mouse model was induced by high-fat diet and low-dose streptozotocin. Samples were obtained from epididymal, subcutaneous and brown adipose tissues. Infiltration of M1/M2 macrophages and inflammatory cytokines were investigated by immunohistochemistry. We then used gene overexpression to investigate the effect of STAMP2 on macrophages infiltration and polarization and inflammatory cytokines expression. Our results showed that infiltration of macrophages, the ratio of M1/M2 macrophages and the expression of pro-inflammatory cytokines were enhanced and STAMP2 was downregulated in adipose tissues of diabetic ApoE−/−/LDLR−/− mice compared with control mice. STAMP2 gene overexpression could significantly reduce macrophages infiltration, the ratio of M1/M2 macrophages and the expression of pro-inflammatory cytokines in epididymal and brown adipose tissues, improving insulin resistance. Our results suggested that STAMP2 gene overexpression may improve insulin resistance via regulating macrophage polarization in visceral and brown adipose tissues.

Expression of STAMP2 in monocytes associates with cardiovascular alterations.

Eur J Clin Invest 2010; 40 (6): 490–496