The clinical value of hepatojugular reflux on congestive heart failure: A meta-analysis.

Background: Hepatojugular reflux is a cardiac physical examination with a long history of use in heart failure diagnosis across many clinical settings. However, the development of new diagnostic methods has thrown the clinical role of hepatojugular reflux into question. Our meta-analysis aimed to determine the diagnostic accuracy of hepatojugular reflux and assess its usefulness in diagnosing congestive heart failure among at-risk patients. Methods: This meta-analysis of studies reporting diagnostic hepatojugular reflux values of patients at risk for congestive heart failure followed PRISMA guidelines. We searched MEDLINE, EMBASE, Web of Science, CENTRAL, and Google Scholar for eligible studies from inception through February 1, 2021. After QUADAS-2 quality assessment, we conducted data synthesis using the random effects model and a hierarchical summary receiver operating characteristic model. As an additional analysis, we sorted the studies by clinical setting and performed synthesis again. We submitted our protocol to PROSPERO (International Prospective Register of Systematic Reviews; ID No. CRD42020215004). Results: The literature search provided 4121 studies for evaluation. Seven studies and their 5195 participants were deemed eligible for synthesis. Clinical diagnosis was the most frequent reference standard. Bivariate random-effects analysis found hepatojugular reflux sensitivity of 0.12, 95% confidence interval (CI) [0.07-0.19], and specificity of 0.96, 95% CI [0.95-0.97]. The DOR was 29.7, 95% CI [18.4-45.3]. The additional analysis of the emergency settings provided a sensitivity of 0.14, 95% CI [0.12-0.17] and specificity of 0.95, 95% CI [0.93-0.96]. Conclusions: Our meta-analysis suggests that hepatojugular reflux has practical value for diagnosis of congestive heart failure with high specificity.

Effects of Low-Dose Colchicine on Serum High-Sensitivity C-Reactive Protein Level in Coronary Artery Disease Patients with Type 2 Diabetes Mellitus and Enhanced Inflammatory Response Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase 2, Dose-Finding Study.

Although cardiovascular mortality in Japan is lower than in other industrialized countries, clinical outcomes in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM) remain poor despite multiple evidence-based drug therapies and interventions. We assumed that part of residual risk in these patients may be attributable to enhanced inflammation, which can be inhibited presumably by colchicine. However, dose-responsiveness of anti-inflammatory effect of colchicine has not been elucidated. Therefore, we designed a multicenter, randomized, double-blinded, parallel-group study to explore the dose-dependent effects of low-dose colchicine on serum high-sensitivity C-reactive protein (hs-CRP) concentration and safety in CAD patients with T2DM and enhanced inflammatory response as a phase 2 study. Enhanced inflammatory response was defined as peripheral white-blood cell count ≥7,000/µL. Patients (N = 63) will be randomly assigned to two doses of colchicine 0.25 mg/day, 0.5 mg/day, or placebo in a 1:1:1 ratio once daily for 12 weeks. Changes in serum hs-CRP levels will be evaluated as the primary endpoint, and changes in flow-mediated vasodilation and plasma myeloperoxidase levels will be evaluated as secondary endpoints. The results of this study will contribute to the development of a protocol for a planned future phase 3 trial to estimate the reduction in CAD. The present study describes the rationale, design, and methods of the trial.

Chronic kidney disease and subclinical lacunar infarction are independently associated with frontal lobe dysfunction in community-dwelling elderly subjects: the Sefuri brain MRI study.

Although recent studies have found that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment in population-based cohorts, the mechanisms of cognitive impairment in subjects with CKD are unclear. We examined 503 elderly subjects (mean age: 72.4 years), who were living independently at home without apparent dementia, using MRI. The subject was judged as having frontal lobe dysfunction if the scores on the modified Stroop test were higher than the fifth quintile for each given decade. Serum creatinine values, measured by the enzymatic method, were used for the Japanese equation of estimated glomerular filtration rate (eGFR). Subjects in the frontal lobe dysfunction group tended to have higher blood pressure, lower eGFR and more lacunar infarcts, and were less educated. When possible confounders were entered into the multivariate logistic regression model, the independent predictors of frontal lobe dysfunction were eGFR (odds ratio 0.854; 95% confidence interval (CI) 0.743-0.983 per 10 ml min(-1) per 1.73 m(2)) and the number of lacunar infarction (odds ratio 1.460; 95% CI 1.127-1.892). The mean of the logarithmically transformed Stroop test scores in the eGFR<60 ml min(-1) per 1.73 m(2) group was 1.376 (95% CI 1.301-1.451), which was significantly higher than that (1.250) for the eGFR 60-89 ml min(-1) per 1.73 m(2) group (95% CI 1.215-1.285) (P=0.009) and tended to be higher than that (1.264) for the eGFR ≥90 ml min(-1) per 1.73 m(2) group (95% CI 1.188-1.340) (analysis of covariance, adjusted for age). The present study showed that CKD and subclinical lacunar infarction independently contributed to frontal lobe dysfunction in healthy elderly subjects.

Association of intima-media thickening of carotid artery with genetic polymorphisms of the regulator of G-protein signaling 2 gene in patients with hypertension and in the general population.

Regulator of G-protein signaling 2 (RGS2) is a key molecule in signal pathways of vasoactive peptides, such as angiotensin II and endothelin 1, and is believed to have an important role in the pathophysiology of atherosclerosis. We have previously reported that common polymorphisms of RGS2 are associated with hypertension in Japanese. In this study, we studied whether the three previously identified common polymorphisms of RGS2 (-638A>G, 1026T>A and 1891-1892delTC) could be implicated in carotid atherosclerosis in Japanese patients with hypertension (459 men and 382 woman) and in a Japanese general population (814 men and 956 woman). We assessed two criteria for carotid atherosclerosis: maximal intima-media thickness (M-IMT) and mean-IMT. When subjects with atherosclerotic lesions were defined as having mean-IMT≥1.0 mm, multivariate logistic regression analysis performed after adjusting for confounding factors showed a significant association of the three common polymorphisms, -638A>G (AA versus AG+GG: odds ratio (OR), 1.55; 95% confidence interval (CI), 1.105-2.185; P=0.0113 only for the general population), 1026T>A (TT versus TA+AA: OR, 1.42; 95% CI, 1.027-1.972; P=0.034 for hypertensive subjects and OR, 1.56; 95% CI, 1.129-2.151; P=0.0071 for the general population), and 1891-1892delTC (II versus ID+DD: OR, 1.44; 95% CI, 1.043-2.008; P=0.028 for hypertensive subjects, OR, 1.32; 95% CI 1.002-1.742; P=0.048 for the total general population and OR 1.59; 95% CI 1.155-2.207; P=0.0047 for the general population), with carotid atherosclerosis. When atherosclerosis was defined as M-IMT 1.0 mm, the values of M-IMT were also significantly different between the three genotypes in the three common polymorphisms. Taken together, these data suggest that genetic polymorphisms in RGS2 are associated with intima-media thickening of carotid artery in humans.

Biological actions of green tea catechins on cardiac troponin C.

BACKGROUND AND PURPOSE: Catechins, biologically active polyphenols in green tea, are known to have a protective effect against cardiovascular diseases. In this study, we investigated direct actions of green tea catechins on cardiac muscle function to explore their uses as potential drugs for cardiac muscle disease. EXPERIMENTAL APPROACH: The effects of catechins were systematically investigated on the force-pCa relationship in skinned cardiac muscle fibres to determine their direct effects on cardiac myofilament contractility. The mechanisms of action of effective catechins were investigated using troponin exchange techniques, quartz crystal microbalance, nuclear magnetic resonance and a transgenic mouse model. KEY RESULTS: (-)-Epicatechin-3-gallate (ECg) and (-)-epigallocatechin-3-gallate (EGCg), but not their stereoismers (-)-catechin-3-gallate and (-)-gallocatechin-3-gallate, decreased cardiac myofilament Ca(2+) sensitivity probably through its interaction with cardiac troponin C. EGCg restored cardiac output in isolated working hearts by improving diastolic dysfunction caused by increased myofilament Ca(2+) sensitivity in a mouse model of hypertrophic cardiomyopathy. CONCLUSIONS AND IMPLICATIONS: The green tea catechins, ECg and EGCg, are Ca(2+) desensitizers acting through binding to cardiac troponin C. These compounds might be useful compounds for the development of therapeutic agents to treat the hypertrophic cardiomyopathy caused by increased Ca(2+) sensitivity of cardiac myofilaments.

Antiproteinuric effect of cilnidipine in hypertensive Japanese treated with renin-angiotensin-system inhibitors - a multicenter, open, randomized trial using 24-hour urine collection.

Sustained proteinuria is an important risk factor for not only renal but also cardiovascular morbidity and mortality. Although inhibitors of the renin-angiotensin system (RAS) have been shown to reduce proteinuria. Monotherapy with those drugs is often insufficient for optimal blood pressure (BP)-lowering and therefore, combined therapy is needed. Recent reports suggested that cilnidipine, a dual L-/N-type calcium channel blocker, has renoprotective effect by dilating both efferent and afferent arterioles. In this study, a multicenter, open, randomized trial was designed to compare the antiproteinuric effect between cilnidipine and amlodipine when coupled with RAS inhibitors in hypertensive patients with significant proteinuria. Proteinuria was evaluated by 24-h home urine collection for all patients. A total of 35 proteinuric (>0.1 g/day) patients with uncontrolled BP (>135/85 mmHg) were randomized to receive either cilnidipine (n = 18) or amlodipine (n = 17) after a 6-month treatment with RAS inhibitors and were followed for 48 weeks. At baseline, the cilnidipine group was older and had lower body mass index (BMI) compared to the amlodipine group. After 32 weeks of treatment, diastolic blood pressure (DBP) was slightly, but significantly reduced, in the cilnidipine group, although systolic blood pressure (SBP) and mean BP did not differ. The urinary protein did not differ at baseline (cilnidipine group 0.48 g/day, amlodipine group 0.52 g/day); however, it significantly decreased in the cilnidipine group (0.22 g/day) compared to the amlodipine group (0.50 g/day) after 48 weeks of treatment. Our findings suggest that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients even undergoing treatment with RAS inhibitors.

Sex differences in the risk profile and male predominance in silent brain infarction in community-dwelling elderly subjects: the Sefuri brain MRI study.

Although brain infarction is more common in men, the male predominance of silent brain infarction (SBI) was inconsistent in the earlier studies. This study was to examine the relationship between sex differences in the risk profile and SBI. We conducted a population-based, cross-sectional analysis of cardiovascular risk factors and SBI on MRI. We asked all the female participants about the age at natural menopause and parity. SBI was detected in 77 (11.3%) of 680 participants (266 men and 414 women) with a mean age of 64.5 (range 40-93) years. In the logistic analysis, age (odds ratio (OR)=2.760/10 years, 95% confidence interval (CI)=2.037-3.738), hypertension (OR=3.465, 95% CI=1.991-6.031), alcohol intake (OR=2.494, 95% CI=1.392-4.466) and smoking (OR=2.302, 95% CI=1.161-4.565) were significant factors concerning SBI. Although SBI was more prevalent among men, this sex difference disappeared on the multivariate model after adjustment for other confounders. In 215 women aged 60 years or older, age at natural menopause, early menopause, duration of menopause, number of children and age at the last parity were not significantly associated with SBI after adjustment for age. Hypertension and age were considered to be the major risk factors for SBI in community-dwelling people. Male predominance in SBI was largely due to higher prevalence of alcohol habit and smoking in men than in women in our population.

Dictyostelium differentiation-inducing factor-1 binds to mitochondrial malate dehydrogenase and inhibits its activity.

We have reported that the differentiation-inducing factors (DIFs) DIF-1 and DIF-3, morphogens secreted from Dictyostelium discoideum, inhibit proliferation of several cancer cells via suppression of the Wnt/beta-catenin signaling pathway. However, the target molecules of DIFs involved in the anti-proliferative effects are still unknown. In the present study, DIF-1-tethered resins were synthesized to explore the target molecules of DIFs, and mitochondrial malate dehydrogenase (mMDH) was identified as one of the target molecules. In the in vitro assay, DIF-1 and other analogs including 2-MIDIF-1, DIF-3, and 6-MIDIF-3 were found to be capable of binding to mMDH but not to cytoplasmic MDH. However, only DIF-1 and 2-MIDIF-1 inhibited the enzymatic activity of mMDH. The effects of DIF analogs on ATP content and cell proliferation were then analyzed using HeLa cells. DIF-1 and 2-MIDIF-1 were found to lower the ATP content and both chemicals inhibited HeLa cell proliferation, suggesting that inhibition of mMDH activity affected cell energy production, probably leading to the inhibition of proliferation. These results suggest that the inhibition of mMDH activity by DIF-1 and 2-MIDIF-1 could be one of the mechanisms to induce anti-proliferative effects, independent of the inhibition of the Wnt/beta-catenin signaling pathway.

Improvement of blood pressure control in a hypertension clinic in Japan: a 15-year follow-up study.

Many guidelines recommended strict blood pressure (BP) control to prevent cardiovascular events. However, BP control in a substantial majority of hypertensives remains to be insufficient. We have determined the trends of BP control of the same patients during 15 years in a hypertension clinic. One hundred three patients (age 32-91, mean 68 +/- 11 years in 2006), who were followed at our hypertension clinic between 1991-2006, were retrospectively investigated. We compared the clinical characteristics of the patients in 2006 to those in 1991, 1996, and 2001, using the averaged BP determined at two occasions of each year for our analysis. The average BP decreased from 144 +/- 17/87 +/- 10 mmHg to 132 +/- 12/75 +/- 10 mmHg (p < 0.01) during the 15 years between 1991 and 2006. When good BP control was defined as < 140/90 mmHg, the rate of patients with good BP control increased from 35% in 1991 to 45% in 1996, to 54% in 2001 (p < 0.01 vs. 1991), and to 72% in 2006 (p < 0.01 vs. 1991). The number of anti-hypertensive drugs used in 2006 significantly increased compared to those in 1991, 1996, and 2001. More specifically, the use of diuretics and alpha-blockers increased significantly during this period. Results suggest that BP control improved in the 15 years studied, and the increased use of the anti-hypertensive drugs, as well as the increased awareness of the importance of strict BP control, seems to have contributed to improve the BP control.

Association of PLA2G7 polymorphisms with carotid atherosclerosis in hypertensive Japanese.

Although the plasma platelet-activating factor-acetylhydrolase (pPAF-AH) gene (PLA2G7) polymorphisms are reportedly associated with atherosclerotic diseases, their effects in hypertensive patients have not been well examined. Thus, we genotyped V279F, a loss-of-function mutation commonly seen in the Japanese, and I198T and A379V commonly seen in Caucasians, and investigated the (1) ethnic differences in the frequencies and (2) association of these variants with prevalence of carotid plaque in 733 treated hypertensive Japanese patients. The distribution of V279F (V allele 75.1% and F allele 24.9%) in hypertensive patients was similar to that previously reported in the healthy Japanese; however, allele frequencies of I198T (I allele 71.7% and T allele 28.3%) and A379V (A allele 84.7% and V allele 15.3%) were markedly different from those reported in Caucasians. In addition, V279F and I198T showed a strong linkage disequilibrium (D'=1.0, r(2)=0.89). The phenotypes showed no difference among genotypes for each polymorphism except for the blood pressure level in I198T in women. Carotid plaque was significantly more prevalent in subjects with 279F and 198T than in those with the wild type among men but not women, whereas A379V did not affect it. In multivariate logistic regression analyses, 279F and 198T were detected as an independent risk factor even after adjustments for other atherosclerotic risk factors in men. Taken together, our data suggest an ethnic difference and the possible involvement of genetic polymorphisms of PLA2G7 in the prevalence of carotid atherosclerosis in the hypertensive Japanese, especially in men.

Hypertension and white matter lesions are independently associated with apathetic behavior in healthy elderly subjects: the Sefuri brain MRI study.

Apathy is defined as a syndrome of primary loss of motivation not attributable to emotional distress, intellectual impairment or consciousness disturbance. The aim of our study was to investigate the effects of vascular risk factors and silent ischemic brain lesions on apathetic behavior of community-dwelling elderly subjects. Brain MRI and other medical examinations were performed on 222 non-demented community-dwelling elderly subjects (96 men and 126 women, average age 70.1 years). The apathy group was defined as the most apathetic quintile determined by Starkstein's apathy scale. Silent infarction, deep white matter lesions (DWMLs) and periventricular hyperintensities were detected in 12.2, 39.2 and 22.5%, respectively. Linear regression analysis (Pearson) revealed that the scores on the apathy scale correlated slightly but significantly with logarithmically transformed scores of the Modified Stroop Test (r=0.135, P=0.045), but not with the Mini-Mental State Examination. The apathy group tended to have more high blood pressure (141.6/82.6 vs. 136.1/79.6 mm Hg), less prevalent hyperlipidemia (18 vs. 35%) and lower serum albumin. Multivariate analysis (the forward stepwise method of logistic analysis) revealed an independent correlation between the apathy and grade of DWMLs (odds ratio 1.826, 95% confidence interval (CI) 1.129-2.953 per grade) or diastolic blood pressure (DBP) (odds ratio 1.055, 95% CI 1.014-1.098 per mm Hg) after adjusting for possible confounders. The mean apathy scale score in the DBP>or=90 mm Hg group was significantly lower (more apathetic) than that in the DBP<80 group (P=0.011, analysis of covariance). This study showed that hypertension and DWMLs are independently associated with apathy in healthy elderly subjects.

Therapeutic effect of {beta}-adrenoceptor blockers using a mouse model of dilated cardiomyopathy with a troponin mutation.

AIMS: Extensive clinical studies have demonstrated that beta-adrenoceptor blocking agents (beta-blockers) are beneficial in the treatment of chronic heart failure, which is due to various aetiologies, including idiopathic dilated cardiomyopathy (DCM) and ischaemic heart disease. However, little is known about the therapeutic efficacy of beta-blockers in the treatment of the inherited form of DCM, of which causative mutations have recently been identified in various genes, including those encoding cardiac sarcomeric proteins. Using a mouse model of inherited DCM with a troponin mutation, we aim to study the treatment benefits of beta-blockers. METHODS AND RESULTS: Three different types of beta-blockers, carvedilol, metoprolol, and atenolol, were orally administered to a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene (TNNT2). Therapeutic effects were examined on the basis of survival and myocardial remodelling. The lipophilic beta(1)-selective beta-blocker metoprolol was found to prevent cardiac dysfunction and remodelling and extend the survival of knock-in mice. Conversely, both the non-selective beta-blocker carvedilol and the hydrophilic beta(1)-selective beta-blocker atenolol had no beneficial effects on survival and myocardial remodelling in this mouse model of inherited DCM. CONCLUSION: The highly lipophilic beta(1)-selective beta-blocker metoprolol, known to prevent ventricular fibrillation via central nervous system-mediated vagal activation, may be especially beneficial to DCM patients showing a family history of frequent sudden cardiac death, such as those with a deletion mutation DeltaK210 in the TNNT2 gene.

The involvement of aldosterone in cyclic stretch-mediated activation of NADPH oxidase in vascular smooth muscle cells.

Increasing evidence suggests that aldosterone is implicated in the pathogenesis of cardiovascular diseases. We examined whether aldosterone contributes to the cyclic stretch (CS)-induced reactive oxygen species (ROS) generation in rat aortic smooth muscle cells (RASMCs). RASMCs were exposed to uniaxial CS and thereafter collected to evaluate the expressions of mRNA or protein relating aldosterone synthesis and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. CS strength-dependently enhanced NADPH oxidase activity. CS induced cytochrome P450 aldosterone synthase (CYP11B2) and increased aldosterone synthesis but did not influence the levels of 11beta-hydroxysteroid dehydrogenase 2 and mineralocorticoid receptor (MR). This CYP11B2 induction was almost completely suppressed by treatment with an extracellular signal-regulated kinase (ERK) inhibitor, U0126, whereas olmesartan, an angiotensin II (Ang II) receptor blocker (ARB), only partially suppressed CS-induced CYP11B2 expression and ERK phosphorylation. A selective MR antagonist, eplerenone (10 micromol l(-1)), significantly attenuated the CS-induced NADPH oxidase activation even in the presence of ARBs. In conclusion, aldosterone synthesis, which is partially independent of Ang II, may have an important role in CS-stimulated ROS generation in cultured RASMCs. We also suggest the potential benefit of eplerenone in the treatment of cardiovascular diseases.

Propyl gallate, a strong antioxidant, increases the Ca2+ sensitivity of cardiac myofilament.

Ca(2+) sensitizers are cardiotonic agents that directly increase the Ca(2+) sensitivity of cardiac myofilament. To find a novel Ca(2+) sensitizer, we have screened a group of phenolic compounds by examining their effects on the Ca(2+)-dependent force generation in cardiac muscle fibers. We found that propyl gallate, a strong antioxidant, increased the Ca(2+) sensitivity of cardiac myofilament in a dose-dependent and reversible manner. The present study indicates that propyl gallate is a novel type of Ca(2+) sensitizer with antioxidant activity, which might be more beneficial for the treatment of congestive heart failure associated with oxidative stress than existing Ca(2+) sensitizers.

Genetic polymorphisms of L-type calcium channel alpha1C and alpha1D subunit genes are associated with sensitivity to the antihypertensive effects of L-type dihydropyridine calcium-channel blockers.

BACKGROUND: The response of blood pressure (BP) to L-type dihydropyridine calcium-channel blockers (dCCBs) differs among individuals. METHODS AND RESULTS: A pharmacogenomic analysis was undertaken in 161 patients with essential hypertension who were treated with dCCBs to study whether genetic polymorphisms of the calcium channel alpha1C and alpha1D subunit genes, CACNA1C and CACNA1D, are associated with the antihypertensive effects of dCCBs. Responders were defined as those in whom systolic BP (SBP) was lowered by more than 20 mmHg or diastolic BP (DBP) was lowered by more than 10 mmHg after treatment with dCCBs. Eleven sequence-proven polymorphisms of CACNA1C and 5 common polymorphisms of CACNA1D chosen from a public database were subjected to genotypic analysis. The comparison of polymorphism prevalence between responders and nonresponders showed significant differences in CACNA1D rs312481G>A and rs3774426C>T, and in CACNA1C 527974G>A. There were significant differences in SBP or DBP between alleles in these single nucleotide polymorphisms (SNPs). A much more significant reduction in BP was observed for the combined presence of these SNPs. CONCLUSIONS: Three SNPs in CACNA1D or CACNA1C are genetic polymorphisms conferring sensitivity to the antihypertensive effects of L-type dCCBs in patients with hypertension. The BP reduction by L-type dCCBs might be predicted by evaluating these polymorphisms.

Knockout of the l-pgds gene aggravates obesity and atherosclerosis in mice.

This study was designed to determine whether lipocalin type-prostaglandin D synthase (l-pgds) deficiency contributes to atherogenesis using gene knockout (KO) mice. A high-fat diet was given to 8-week-old C57BL/6 (wild type; WT), l-pgds KO (LKO), apolipoprotein E (apo E) KO (AKO) and l-pgds/apo E double KO (DKO) mice. The l-pgds deficient mice showed significantly increased body weight, which was accompanied by increased size of subcutaneous and visceral fat tissues. Fat deposition in the aortic wall induced by the high-fat diet was significantly increased in LKO mice compared with WT mice, although there was no significant difference between AKO and DKO mice. In LKO mice, atherosclerotic plaque in the aortic root was also increased and, furthermore, macrophage cellularity and the expression of pro-inflammatory cytokines such as interleukin-1beta and monocyte chemoattractant protein-1 were significant increased. In conclusion, l-pgds deficiency induces obesity and facilitates atherosclerosis, probably through the regulation of inflammatory responses.

Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects.

Recent studies suggest that lipocalin-type prostaglandin (PG) D synthase (L-PGDS), which converts PGH2 to PGD2, is implicated in the pathogenesis of atherosclerosis. However, clinical evidence for the association between serum L-PGDS levels and atherosclerosis has not been reported. In this study, we measured the serum L-PGDS concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and investigated the association with traditional cardiovascular risk factors and surrogate atherosclerotic indices, such as the maximum score of the intima-media complex thickness of the carotid artery (C-IMT(max)) and the brachial-ankle pulse wave velocity (ba-PWV), in 500 non-treated asymptomatic subjects. The serum concentration of L-PGDS was 0.56+/-0.01 (mean+/-SEM, range 0.25-1.27, median 0.54) mg/L. Serum L-PGDS levels increased with age and were higher in men than in women. Serum L-PGDS was higher in subjects with hypertension and increased with increasing numbers of the traditional atherosclerotic risk factors. When the subjects were divided into four groups according to the levels of serum L-PGDS, the age-adjusted values of C-IMT(max) and ba-PWV were significantly increased in subjects with higher serum L-PGDS levels (quartile 3 and quartile 4) compared to those in the lowest quartile (quartile 1), for both genders. Multiple regression analysis including risk factors revealed that serum L-PGDS was an independent determinant for ba-PWV (beta=0.130, p<0.001). Serum L-PGDS tended to associate with C-IMT(max) but was not statistically significant (beta=0.084, p=0.075). In conclusion, our results suggest that an increase in serum L-PGDS concentration is associated with the progression of atherosclerosis.

Celecoxib-induced degradation of T-cell factors-1 and -4 in human colon cancer cells.

We examined the effect of celecoxib on the expression of T-cell factors (TCFs) to clarify the mechanism by which celecoxib suppress beta-catenin/TCF-dependent transcriptional activity without reducing the level of beta-catenin protein, using HCT-116 cells. Celecoxib suppressed the expression of TCF-1 and TCF-4 in a time-dependent manner. Pretreatment of cells with the proteasome inhibitor MG132 inhibited the loss of TCF-1 and TCF-4 induced by celecoxib, suggesting that celecoxib induced the proteasome-dependent degradation of TCF-1 and TCF-4. Beta-catenin/TCF-dependent transcriptional activity was significantly decreased after the treatment with celecoxib for 6 h and the pretreatment of the cells with MG132 attenuated the effect of celecoxib. Further, celecoxib also suppressed the expression of TCF-1 and TCF-4 in another colon cancer cell line, DLD-1. Our results suggest that TCF-1 and TCF-4 degradation may involve the inhibition of the Wnt/beta-catenin signaling pathway induced by celecoxib.

Associations of hypertension and its complications with variations in the xanthine dehydrogenase gene.

Hyperuricemia and oxidative stress participate in the pathophysiology of hypertension and its complications. Xanthine dehydrogenase (XDH) produces urate and, in its oxidase isoform, reactive oxygen species. Here we have studied whether or not the genetic variations in XDH could be implicated in hypertension and its complications. By sequencing the promoter region and all exons of XDH in 48 subjects, we identified three missense mutations (G172R, A932T, N1109T) in a heterozygous state in addition to 34 variations, including 15 common single nucleotide polymorphisms (SNPs). The three missense mutations and eight common SNPs (11488C>G, 37387A>G, 44408A>G, 46774G>A, 47686C>T, 49245A>T, 66292C>G, and 69901A>C) were genotyped in 953 hypertensive Japanese subjects and in 1,818 subjects from a general Japanese population. Four hypertensive patients with rare missense mutations (G172R or N1109T) in homozygous form had severe hypertension. Multivariate logistic regression analysis showed a significant association of three SNPs with hypertension in men: 47686C>T (exon 22, odds ratio [OR]: 1.52, p = 0.047) and 69901A>C (intron 31, OR: 3.14, p = 0.039) in the recessive model, and 67873A>C (N1109T) (exon 31, OR: 1.84, p = 0.018) in the dominant model. After full adjustment for all confounding factors, only one polymorphism (69901A>C) was found to be associated with carotid atherosclerosis in the dominant model (p = 0.028). Multiple logistic regression analysis showed that one SNP (66292C>G) was significantly associated with chronic kidney disease (CKD: estimated creatinine clearance < 60 ml/min) in the recessive model (p = 0.0006). Our results suggest that genetic variations in XDH contribute partly to hypertension and its complications, including atherosclerosis and CKD.