YangXin Chen

CRP regulates the expression and activity of tissue factor as well as tissue factor pathway inhibitor via NF‐κB and ERK 1/2 MAPK pathway

It was found that C‐reactive protein (CRP) could significantly increase the expression and activity of tissue factor (TF), but decrease that of tissue factor pathway inhibitor (TFPI) in human umbilical vein endothelial cells (HUVECs) in dose‐ and time‐dependent manners, which could be antagonized by PDTC and U0126. CRP could also increase protein expression of phosphorylated nuclear factor‐kappaB (NF‐κB), IκB‐α and ERK1/2 in dose‐ and time‐dependent manner. In addition, neutralizing antibody to CD32 (FcgammaR II) could significantly attenuate the expression and activity of TF and TFPI induced by CRP. These results suggest that CRP may promote coagulation by enhancing the expression and activity of TF and reducing that of TFPI by activating NF‐κB and extracellular signal‐regulated kinase via FcgammaR II.

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 can upregulate VEGF expression to promote ADSC-induced angiogenesis by activating HIF-1α via CD64/PI3k/Akt and MAPK/ERK signaling pathways

BackgroundProliferation of the vasa vasorum has been implicated in the pathogenesis of atherosclerosis, and the vasa vasorum is closely associated with resident stem cells within the vasculature. C-reactive protein (CRP) is positively correlated with cardiovascular disease risk, and our previous study demonstrated that it induces inflammatory reactions of perivascular adipose tissue by targeting adipocytes.MethodsHere we investigated whether CRP affected the proliferation and proangiogenic paracrine activity of adipose-derived stem cells (ADSCs), which may contribute to vasa vasorum angiogenesis.ResultsWe found that CRP did not affect ADSC apoptosis, cell cycle, or proliferation but did increase their migration by activating the PI3K/Akt pathway. Our results demonstrated that CRP can upregulate vascular endothelial growth factor-A (VEGF-A) expression by activating hypoxia inducible factor-1α (HIF-1α) in ADSCs, which significantly increased tube formation on Matrigel and functional vessels in the Matrigel plug angiogenesis assay. The inhibition of CRP-activated phosphorylation of ERK and Akt can suppress CRP-stimulated HIF-1α activation and VEGF-A expression. CRP can also stimulate proteolytic activity of matrix metalloproteinase-2 in ADSCs. Furthermore, CRP binds activating CD64 on ADSCs, rather than CD16/32.ConclusionOur findings implicate that CRP might play a role in vasa vasorum growth by activating the proangiogenic activity of ADSCs.

Local activation of cardiac stem cells for post-myocardial infarction cardiac repair

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue‐specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time‐consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC‐based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post‐MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC‐based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.

Value of BNP and tumour marker CA125 in patients with heart failure.

Objective — The objective was to study the association between B-type natriuretic peptide (BNP) and tumour markers and heart failure (HF) to evaluate the value of BNP and carbohydrate antigen 125 (CA125) in HF patients. Design and setting — A university hospital-based cross-over study of 285 subjects (157 men and 128 women) in HF, chronic obstructive pulmonary disease (COPD), mild-mid pulmonary hypertension patients and control subjects. Results — CA125 and BNP were significantly higher in the HF group than in the non-HF group and in severe HF than in mild HF (P< 0.01). No changes were observed in other tumour markers. CA125 and BNP decreased obviously after clinical improvement by aggressive treatment (P< 0.01). Left ventricular ejection fraction correlated positively with CA125 (r= 0.789, P < 0.01) and BNP (r= 0.730, P< 0.01) in left heart failure patients, but not in other patients. BNP and CA125 had better accuracy and positive predictive value in diagnosing HF from the characteristic receiver-operator curve. Conclusions — CA125 and BNP are markedly elevated in heart failure and closely reflect heart function. They are better markers in evaluating the efficiency of short-term therapy. Detecting BNP combined with CA125 may be more valuable than only detecting BNP or CA125 for diagnosing HF and evaluating the efficiency of treatment.

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.

Angiotensin II Receptor Blocker Attenuates Intrarenal Renin-Angiotensin-System and Podocyte Injury in Rats with Myocardial Infarction

The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague–Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16ink4a, decreased immunostaining for Wilms’ tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2’-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.

Roles of brain and muscle ARNT‐like 1 and Wnt antagonist Dkk1 during osteogenesis of bone marrow stromal cells

Many studies have demonstrated that the clock gene, brain and muscle ARNT‐like 1 (Bmal1), is directly related to bone ageing by affecting age‐related changes to mesenchymal stem cells (MSCs). As a main developmental signal, Wnt may play an important role in this process. Here, we have aimed to elucidate whether Bmal1 positively regulates osteogenesi via Wnt pathways.

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.

Endogenous pro-resolving and anti-inflammatory lipid mediators: The new hope of atherosclerotic diseases

Atherosclerosis is a complex disease process in which genetic, lipid, cellular, and immunological factors combine to determine the location, severity, and timing of lesion development and clinical events. It has been demonstrated, however, that inflammation governed atherosclerosis during the course of development of atherosclerosis. It has also been demonstrated to be effective to decrease the cardiovascular events and improve the prognosis of atherosclerotic diseases by regulating inflammatory reaction (e.g., statins). However, endogenous mechanisms of limiting inflammation in atherosclerosis are still unclear. Recent studies showed that lipoxidase/leukotrienes (LOX/LTs) pathway played important role in the ignition and development of atherosclerosis, whereas resolvins (E-series resolvins and D-series resolvins) and protectins [protectin D1 (PD1) and neuroprotectin D1 (NPD1)], endogenous lipid-derived mediators, inhibited inflammation through pro-resolution and counter-modulating immune inflammation reaction in atherosclerosis. Hence, we hypothesize that increased endogenous lipid mediators mentioned above play a vital role in anti-atherosclerosis and plaque stabilization through pro-resolution and anti-inflammation by LOX/LTs pathway. In addition, we predict that the endogenous lipid mediators may be a new target for treatment of atherosclerotic diseases.