Standardized incidence ratios (SIRs) of cancer sites among heart, kidney, and liver between 2001 and 2012, NHIRD.

<p>Standardized incidence ratios (SIRs) of cancer sites among heart, kidney, and liver between 2001 and 2012, NHIRD.</p

Characterisstics of recipients of heart, kidney and liver transplants in Taiwan between 2001 and 2012.

<p>Characterisstics of recipients of heart, kidney and liver transplants in Taiwan between 2001 and 2012.</p

Risk of cancer among Taiwanese recipients.

<p>(a). Cancer risk for total recipients. (b), (c), and (d). Cancer risk for heart, kidney, and liver recipients.</p

Risk factors for selected cancer in transplanted recipients.

<p>Risk factors for selected cancer in transplanted recipients.</p

Heart, kidney, and liver transplantations performed during the study period.

<p>(a). Transplantations stratified by the organ. (b), (c), and (d). Heart, kidney, and liver transplantations stratified by sex. The purple line indicates the male:female ratio.</p

Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells

<div><p>Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by <i>in vitro</i> and <i>in vivo</i> analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. <i>In vivo</i>, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved neovascularization in hindlimb ischemia mice; this effect may have been mediated by increased CXCR4 expression in EPCs.</p></div

GroEL1, from <em>Chlamydia pneumoniae</em>, Induces Vascular Adhesion Molecule 1 Expression by p37^AUF1 in Endothelial Cells and Hypercholesterolemic Rabbit

<div><p>The expression of vascular adhesion molecule-1 (VCAM-1) by endothelial cells may play a major role in atherogenesis. The actual mechanisms <em>of chlamydia pneumoniae</em> (<em>C. pneumoniae</em>) relate to atherogenesis are unclear. We investigate the influence of VCAM-1 expression in the GroEL1 from <em>C. pneumoniae</em>-administered human coronary artery endothelial cells (HCAECs) and hypercholesterolemic rabbits. In this study, we constructed the recombinant GroEL1 from <em>C. pneumoniae</em>. The HCAECs/THP-1 adhesion assay, tube formation assay, western blotting, enzyme-linked immunosorbent assay, actinomycin D chase experiment, luciferase reporter assay, and immunohistochemical stainings were performed. The results show that GroEL1 increased both VCAM-1expression and THP-1 cell adhesives, and impaired tube-formation capacity in the HCAECs. GroEL1 significantly increased the VCAM-1 mRNA stability and cytosolic AU-binding factor 1 (AUF1) level. Overexpression of the p37^AUF1 significantly increased VCAM-1 gene expression in GroEL1-induced bovine aortic endothelial cells (BAECs). GroEL1 prolonged the stability of VCAM-1 mRNA by increasing both p37^AUF1 and the regulation of the 5′ untranslated region (UTR) of the VCAM-1 mRNA in BAECs. In hypercholesterolemic rabbits, GroEL1 administration enhanced fatty-streak and macrophage infiltration in atherosclerotic lesions, which may be mediated by elevated VCAM-1 expression. In conclusion, GroEL1 induces VCAM-1 expression by p37^AUF1 in endothelial cells and enhances atherogenesis in hypercholesterolemic rabbits.</p> </div

The 5′ UTR flanking sequence of VCAM-1 mRNA conferred P37^AUF1-responsiveness in the BAECs.

<p>(A) The BAECs were transfected with the 4His-A-AUF1-p37 plasmid (p37^AUF1), 4His-A-AUF1-p40 plasmid (p40^AUF1), 4His-A-AUF1-p42 plasmid (p42^AUF1), or 4His-A-AUF1-p45 plasmid (p45^AUF1). The level of VCAM-1 mRNA were analyzed using real-time PCR after transfectiuon for 24 hours. (B) The VCAM-1 mRNA stability was analyzed using an actinomycin D chase experiment in the AUF1-transfected BAECs. (C) Schematic representation of the various plasmids containing the luciferase and UTR of the VCAM-1 mRNA. Control plasmid: pcDNA™ 3.1 plasmid; construct A, CMV-Luciferase plasmid; construct B, CMV-Luciferase-VCAM1 5′UTR (sense) plasmid; construct C, CMV-Luciferase-VCAM1 5′UTR (antisense) plasmid; construct D, CMV-Luciferase-VCAM1 3′UTR (sense) plasmid; construct E, CMV-Luciferase-VCAM1 3′UTR (antisense) plasmid. (D), BAECs were co-transfected with the CMV-Luciferase-VCAM1 UTR plasmid, the β-galactosidase reporter plasmid, and the 4His-A-AUF1 plasmid. Uniform transfection efficiencies were confirmed using a β-galactosidase reporter plasmid. The luciferase activity was quantified by luminometry. Data are expressed as relative luciferase units, presented as the mean ± SEM and represent the results of three independent experiments (*<i>P</i><0.05 was considered significant and n = 3).</p

The NADPH oxidase-related pathway contribute to decreased tube formation in EPCs under high concentrated oxLDL.

<p>(A) EPCs were pretreated with DPI or APO for 1 hour prior to treatment with 5 or 50 μg/mL oxLDL for 24 hours. <i>In vitro</i> angiogenesis was assayed using ECMatrix gel. Data were expressed as the mean ± SEM of three experiments performed in triplicate. *<i>p</i> < 0.05 was considered significant. (B) EPCs were transfected with gp91^phox siRNA, the total gp91^phox protein were analyzed using western blotting. (C) EPCs were pretreated with DPI, LOX-1 blocking antibody for 1 hour or transfected with gp91^phox siRNA prior to 50 μg/mL of oxLDL treatment, subsequently eNOS and Akt activation (phosphorylation) were analyzed by Western blot. Total eNOS, Akt, and β-actin protein levels were used as loading controls. The graph showed the quantitative activation of eNOS (phospho-eNOS/total-eNOS ratio) and Akt (phospho-Akt/total-Akt ratio) density in oxLDL-treated EPCs. (D) EPCs were pretreated with 20 μM Rac1 inhibitor for 1 hour or transfected with gp91^phox siRNA prior to 50 μg/mL oxLDL treatment for 12 hours, subsequently membrane LOX-1 expression was analyzed by Western blot. β-actin protein levels were used as a loading control.</p

p38 MAPK- and SAPK/JNK-related pathways contribute to increased tube formation in EPCs under low concentrated oxLDL.

<p>(A) Following treatment of EPCs with 0–50 μg/mL of oxLDL for 4 hours, the phosphorylation of p38 MAPK, SAPK/JNK and ERK1/2 were analyzed by Western blot. The total p38 MAPK, SAPK/JNK, ERK1/2, and β-actin protein levels were used as loading controls. The graph showed the quantitative activation of p38 MAPK (phospho-p38MAPK/total- p38MAPK ratio), SAPK/JNK (phospho-SAPK/JNK/total-SAPK/JNK ratio), and Akt (phospho-ERK1/2/total-ERK1/2 ratio) density in oxLDL-treated EPCs. (B) EPCs were pretreated with SP600125, PD98059, or SB203580 for 1 hour prior to treatment with 5 or 50 μg/mL oxLDL for 24 hours. (C) Treatment of SP600125, PD98059, or SB203580 alone for 24 hours. <i>In vitro</i> angiogenesis was assayed using ECMatrix gel. (D) EPCs were pretreated with SP600125 or SB203580 for 1 hour prior to treatment with 5 μg/mL oxLDL for 24 hours. The NO-containing conditional medium was analyzed using electron spin resonance spectroscopy. Data are expressed as the mean ± SEM of three experiments performed in triplicate. *<i>p</i> < 0.05 was considered significant. (E) EPCs were pretreated with SP600125 or SB203580 for 1 hour prior to treatment with 5 μg/mL oxLDL for 2 hours, subsequently Akt activation (phosphorylation) was analyzed by Western blot. Total Akt protein levels were used as loading controls.</p