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Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide (CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)(n) in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)(n)>or=30 and S allele means (GT)n<30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P=0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P<0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P<0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P=0.005). A longer length polymorphism with (GT)(n) >or=30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.

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There are focal areas in the aorta wtth an enhanced endothelial permeability to macromolecules, as indicated by the focal uptake of the proteln-blndlng azo dye Evans blue In vivo. These areas exhibit high rates of endothelial cell turnover and a number of structural characteristics In en face endothelial morphology. To determine the relationship of endothelial cell death to macromolecular leakage at the level of individual endothelial cells, thoracic aortas of 12 adult male Sprague-Dawley rats were studied at 3 to 5 minutes after Intravenous administration of Evans blue-albumin ( 1 In previous studies, 2 -5 we demonstrated that an extremely high percentage of dividing endothelial cells in the mitotic M phase exhibited junctional leakage to macromolecules, i.e., 91 % for Evans blue-albumin (EBA) and 78% for Lucifer yellow-tow density lipoprotein (LY-LDL), but these mitotic endothelial cells with tracer leakage contributed to only 23% of all EBA leaky foci and 42% of all LY-LDL leaky foci. Thus, mitotic endothelial cells alone cannot explain all the macromolecular leaks observed in the aorta.A small, but significant, fraction of endothelial cells can be found to undergo turnover in normal rat aortic endothelium.8 Studies by Hansson et al. 6 have shown that endothelial cell death and replication are topographically clustered phenomena. There seems to be a spatial association between clusters of dead endothelial cells and clusters of replicating endothelial cells. The codistribution of dead and replicating cells in the aortic endothelium suggests that, in adult animals, the role of

Aims: We investigated the role of transient receptor potential vanilloid receptor type 1 (TRPV1) in simvastatin-mediated activation of endothelial nitric oxide synthase (eNOS) and angiogenesis. Methods: Fluo-8 NW assay was for Ca 2+ detection; Griess's assay was for NO bioavailability; Western blotting and immunoprecipitation were for protein phosphorylation and interaction; tube formation and Matrigel plug assay were for angiogenesis. Results: In endothelial cells (ECs), treatment with simvastatin time-dependently increased intracellular level of Ca 2+ . Pharmacological inhibition or genetic disruption of TRPV1 abrogated simvastatin-mediated elevation of intracellular Ca 2+ in ECs or TRPV1-transfected HEK293 cells. Loss of TRPV1 function abolished simvastatin-induced NO production and phosphorylation of eNOS and calmodulin protein kinase II (CaMKII) in ECs and in aortas of mice. Inhibition of TRPV1 activation prevented the simvastatin-elicited increase in the formation of TRPV1-Akt-CaMKII-AMPK-eNOS complex. In mice, Matrigel plug assay showed that simvastatin-evoked angiogenesis was abolished by TRPV1 antagonist and genetic ablation of TRPV1. Additionally, our results demonstrated that TRP ankyrin 1 (TRPA1) is the downstream effector in the simvastatin-activated TRPV1-Ca 2+ signalling and in the consequent NO production and angiogenesis as evidence by that re-expression of TRPA1 further augmented simvastatin-elicited Ca 2+ influx in TRPV1-expressed HEK293 cells and ablation of TRPA1 function profoundly inhibited the simvastatin-induced increase in the phosphorylation of eNOS and CaMKII, formation of TRPV1-Akt-CaMKII-AMPK-eNOS complex, NO bioavailability, tube formation and angiogenesis in ECs or mice. Conclusion: Simvastatin-induced Ca 2+ influx may through the activation of TRPV1-TRPA1 signalling, which leads to phosphorylation of CaMKII, increases in the formation of TRPV1-CaMKII-AMPK-eNOS complex, eNOS activation, NO production and, ultimately, angiogenesis in ECs.

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BackgroundsLower health literacy (HL) is associated with several cardiovascular disease (CVD) risk factors such as diabetes, hypertension, and metabolic syndrome (MS). The aim of our study was to investigate the association between HL and the Framingham 10-year risk score of CVD.MethodsFrom 2015–2016, 1010 subjects aged 23 to 88 years receiving health check-up in Taipei Veterans General Hospital had complete clinical evaluations and laboratory examinations. Fatty liver was diagnosed by ultrasonography. The short form questionnaire adapted from the Mandarin Health Literacy Scale was used to assess HL. The Framingham risk score was calculated by patient characteristics.ResultsSubjects with higher BMIs were associated with lower HL scores. The proportion of subjects with MS was higher in the lower health literacy score group (≤ 9) at 28.8%; further analysis found that lower HL was significantly associated with MS in women but not in men. The Spearman’s rho demonstrated that the HL score was significantly associated with the BMI-based (rho = -0.11; P < 0.001) or lipid-based (rho = -0.09; P < 0.004) Framingham risk score.ConclusionsHigher HL scores were associated with less CVD risk such as lower BMIs, less MS in women, and less fatty liver disease. Furthermore, HL had an inverse association with the Framingham risk score as expected. Therefore, HL in patients with CVD risk should be improved and considered as an important issue in terms of CVD reduction.

SummaryBackground: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in patients with coronary artery disease (CAD) has not been investigated.Hypothesis: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis.Methods: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group 1 (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); Group 2 (n = 51): patients with significant CAD (≥ 50% stenosis of major coronary arteries). Plasma levels of ADMA and L-arginine were determined by high-performance liquid chromatography. In addition, we used coronary atherosclerotic score to assess the extent and severity of CAD.Results: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66