Xiaojian Wang

Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: a meta-analysis of randomized placebo-controlled trials

BACKGROUND The effect of isoflavone on endothelial function in postmenopausal women is controversial. OBJECTIVE The objective of this study was to evaluate the effect of oral isoflavone supplementation on endothelial function, as measured by flow-mediated dilation (FMD), in postmenopausal women. DESIGN A meta-analysis of randomized placebo-controlled trials was conducted to evaluate the effect of oral isoflavone supplementation on endothelial function in postmenopausal women. Trials were searched in PubMed, Embase, the Cochrane Library database, and reviews and reference lists of relevant articles. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effects models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS A total of 9 trials were reviewed in the present meta-analysis. Overall, the results of the 9 trials showed that isoflavone significantly increased FMD (WMD: 1.75%; 95% CI: 0.83%, 2.67%; P = 0.0002). Meta-regression analysis indicated that the age-adjusted baseline FMD was inversely related to effect size. Subgroup analysis showed that oral supplementation of isoflavone had no influence on FMD if the age-adjusted baseline FMD was > or = 5.2% (4 trials; WMD: 0.24%; 95% CI: -0.94%, 1.42%; P = 0.69). This improvement seemed to be significant when the age-adjusted baseline FMD levels were <5.2% (5 trials; WMD: 2.22%; 95% CI: 1.15%, 3.30%; P < 0.0001), although significant heterogeneity was still detected in this low-baseline-FMD subgroup. CONCLUSIONS Oral isoflavone supplementation does not improve endothelial function in postmenopausal women with high baseline FMD levels but leads to significant improvement in women with low baseline FMD levels.

Effect of soy isoflavones on blood pressure: A meta-analysis of randomized controlled trials

BACKGROUND AND AIM The effect of soy isoflavones on blood pressure is controversial. The objective of this study was to evaluate the effect of dietary soy isoflavones on blood pressure. METHODS AND RESULTS Trials were searched in PubMed, the Cochrane Library, Embase and references cited in related reviews and studies. A total of eleven trials were reviewed. Meta-analysis results showed a mean decrease of 2.5 mm Hg (95% CIs, - 5.35 to 0.34 mm Hg; P = 0.08) for systolic blood pressure and 1.5 mm Hg (95% CIs, - 3.09 to 0.17 mm Hg; P = 0.08) for diastolic blood pressure in the soy isoflavones-treated group compared to placebo. Meta-regression and subgroup analyses indicated that blood pressure status was a significant predictor of heterogeneity for the effect of soy isoflavones on blood pressure. Subgroup analysis of hypertensive subjects revealed that a greater blood pressure reduction was identified in the soy isoflavone-treated group compared to placebo (5 trials; SBP: - 5.94, 95% CIs [- 10.55, - 1.34] mm Hg, P = 0.01; DBP: - 3.35, 95% CIs [- 6.52, - 0.19] mm Hg, P = 0.04). In contrast, treatment with soy isoflavones did not lead to a significant reduction in blood pressure in normotensive subjects (6 trials; SBP: 0.29, 95% CIs [- 2.39, 2.97] mm Hg, P = 0.83; DBP: - 0.43, 95% CIs [- 1.66, 0.81] mm Hg, P = 0.50). CONCLUSION Soy isoflavones had an effect of lowering blood pressure in hypertensive subjects, but not in normotensive subjects. Larger trials need to be carried out to confirm the present findings.

Polymorphisms of ACE2 Gene are Associated With Essential Hypertension and Antihypertensive Effects of Captopril in Women

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the renin‐angiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two case‐control studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6‐fold risk for hypertension in women (95% confidence interval (CI), 1.13–2.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34‐fold (95% CI, 1.75–4.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

A Functional Variant of NEDD4L Is Associated With Hypertension, Antihypertensive Response, and Orthostatic Hypotension

NEDD4L is involved in the regulation of plasma volume and blood pressure by controlling cell surface expression of the kidney epithelial Na+ channel. Previously, the cryptic splice variant rs4149601(G/A) A allele of NEDD4L, generating isoform I, was estimated to decrease blood pressure by downregulating Na+ reabsorption. However, a recent functional study showed that isoform I should lead to abnormal Na+ reabsorption increases by antagonistically downregulating epithelial Na+ channel activities. To determine whether the variant rs4149601 A allele is a risk factor for hypertension, has an impact on the antihypertensive response to hydrochlorothiazide, and is associated with orthostatic hypotension, we performed a case-control study of hypertension (n=1686), a 4-week clinical trial (n=542), and a case-control study of orthostatic hypotension (n=793) in Chinese subjects. We found that the A allele was significantly associated with hypertension after appropriate adjustment (odds ratio: 1.39; 95% CI: 1.13 to 1.72; P=0.002). The blood pressure reduction in A carriers after hydrochlorothiazide treatment was greater than that in GG carriers, with differences of 6.1 mm Hg (P=0.009) in systolic blood pressure and 2.7 mm Hg (P=0.027) in diastolic blood pressure. The A allele was significantly associated with orthostatic hypotension after adjustment for cardiovascular risk factors (odds ratio: 0.68; 95% CI: 0.48 to 0.98; P=0.039). In conclusion, rs4149601 is a genetic risk factor for hypertension and a protective factor against orthostatic hypotension in hypertensive subjects, and the antihypertensive response to hydrochlorothiazide is more sensitive in A allele carriers than in GG carriers. Consequently, the A allele may be a useful marker for predicting hypertension, orthostatic hypotension, and antihypertensive response to hydrochlorothiazide.

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is characterized by increased ventricular wall thickness that cannot be explained by underlying conditions, cadiomyocyte hypertrophy and disarray, and increased myocardial fibrosis. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that more genes may be involved. Nexilin, encoded by NEXN, is a cardiac Z-disc protein recently identified as a crucial protein that functions to protect cardiac Z-discs from forces generated within the sarcomere. We screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease. Two missense mutations, c.391C>G (p.Q131E) and c.835C>T (p.R279C), were identified in exons 5 and 8 of NEXN, respectively, in two probands. Each of the two mutations segregated with the HCM phenotype in the family and was absent in 384 control chromosomes. In silico analysis revealed that both of the mutations affect highly conserved amino acid residues, which are predicted to be functionally deleterious. Cellular transfection studies showed that the two mutations resulted in local accumulations of nexilin and that the expressed fragment of actin-binding domain containing p.Q131E completely lost the ability to bind F-actin in C2C12 cells. Coimmunoprecipitation assay indicated that the p.Q131E mutation decreased the binding of full-length NEXN to α-actin and abolished the interaction between the fragment of actin-binding domain and α-actin. Therefore, the mutations in NEXN that we describe here may further expand the knowledge of Z-disc genes in the pathogenesis of HCM.

MiR-221 promotes cardiac hypertrophy in vitro through the modulation of p27 expression.

Cardiac hypertrophy has been known as an independent predictor for cardiovascular morbidity and mortality. Molecular mechanisms underlying the development of heart failure remain elusive. Recently, microRNAs (miRs) have been established as important regulators in cardiac hypertrophy. Here, we reported miR‐221 was up‐regulated in both transverse aortic constricted mice and patients with hypertrophic cardiomyopathy (HCM). Forced expression of miR‐221 by transfection of miR‐221 mimics increased myocyte cell size and induced the re‐expression of fetal genes, which were inhibited by the knockdown of endogenous miR‐221 in cardiomyocytes. The TargetScan algorithm‐based prediction identified that p27, a cardiac hypertrophic suppressor, is the putative target of miR‐221, which was confirmed by luciferase assay and Western blotting.

MiR-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1.

The molecular mechanisms that drive the development of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) remain elusive. Accumulated evidence suggests that microRNAs are essential regulators of cardiac remodelling. We have been suggested that microRNAs could play a role in the process of HCM. To uncover which microRNAs were changed in their expression, microRNA microarrays were performed on heart tissue from HCM patients (n = 7) and from healthy donors (n = 5). Among the 13 microRNAs that were differentially expressed in HCM, miR‐451 was the most down‐regulated. Ectopic overexpression of miR‐451 in neonatal rat cardiomyocytes (NRCM) decreased the cell size, whereas knockdown of endogenous miR‐451 increased the cell surface area. Luciferase reporter assay analyses demonstrated that tuberous sclerosis complex 1 (TSC1) was a direct target of miR‐451. Overexpression of miR‐451 in both HeLa cells and NRCM suppressed the expression of TSC1. Furthermore, TSC1 was significantly up‐regulated in HCM myocardia, which correlated with the decreased levels of miR‐451. As TSC1 is a known positive regulator of autophagy, we examined the role of miR‐451 in the regulation of autophagy. Overexpression of miR‐451 in vitro inhibited the formation of the autophagosome. Conversely, miR‐451 knockdown accelerated autophagosome formation. Consistently, an increased number of autophagosomes was observed in HCM myocardia, accompanied by up‐regulated autophagy markers, and the lipidated form of LC3 and Beclin‐1. Taken together, our findings indicate that miR‐451 regulates cardiac hypertrophy and cardiac autophagy by targeting TSC1. The down‐regulation of miR‐451 may contribute to the development of HCM and may be a potential therapeutic target for this disease.

Association of Intergenic Polymorphism of Organic Anion Transporter 1 and 3 Genes With Hypertension and Blood Pressure Response to Hydrochlorothiazide

BACKGROUND Organic anion transporter (OAT) 1 and OAT3, encoded by a tightly linked gene pair, play a key role in renal secretion of diuretics. However, no study has yet examined the influence of OAT1 and OAT3 polymorphisms on high blood pressure (BP) and the response to thiazide diuretics. We hypothesized that intergenic polymorphisms between OAT1 and OAT3 might be associated with adult hypertension and the antihypertensive effects of hydrochlorothiazide (HCTZ). METHODS The association of an intergenic polymorphism (rs10792367) with hypertension risk was investigated in two independent case-control studies (n = 1,592 and 602), and then a combined analysis was performed for improving power (1,106 cases and 1,088 controls) with adjustment for geographic location. Two clinical trials (n = 542 and 274) were conducted in untreated hypertensive patients for the association of rs10792367 with antihypertensive responses to 4 and 8 weeks of HCTZ treatment. RESULTS No significant association was found between rs10792367 and hypertension after adjustment for conventional risk factors in either the two populations, respectively, or the combined two population. After adjustment for pretreatment BP and other confounders, HCTZ-induced reduction in systolic BP was 4.8 mm Hg (P = 0.006, first trial) and 6.1 mm Hg (P = 0.003, in second trial) lower, respectively, in C allele carriers than in GG carriers in the two clinical trials. CONCLUSIONS Intergenic polymorphism rs10792367 between OAT1 and OAT3 is not associated with hypertension, but appears to be involved in between-individual variations in antihypertensive responses to HCTZ.

Phosphodiesterase 4D gene polymorphism is associated with ischaemic and haemorrhagic stroke

It has been reported that the variants of the PDE4D (phosphodiesterase 4D) gene are associated with stroke, especially with the combination of cardio-embolic and carotid stroke in the Icelandic population, but it is still very controversial as to whether PDE4D is a susceptible gene for stroke in other populations. In the present study, we tested whether the PDE4D gene variation also confers stroke risk in a Chinese population. Our hypothesis was tested in a case-control study of a Chinese population comprising 639 stroke patients (including 253 with cerebral thrombosis, 171 with lacunar infarction and 215 with intracerebral haemorrhage) and 887 healthy controls. Three SNPs (single nucleotide polymorphisms) (rs966221, rs456009 and rs2910829) in PDE4D were chosen based on the significant association with stroke reported previously in a Western population, and these were genotyped using PCR/RFLP (restriction-fragment-length polymorphism) and confirmed by sequencing. We found that only SNP83 (rs966221) was associated with stroke. Allele C of rs966221 is a risk allele, conferring an increased risk for atherothrombotic strokes [OR (odds ratio), 1.51; 95% CI (confidence interval), 1.09-2.10] independent of conventional risk factors. Haplotype analysis confirmed that haplotype G-C-C was associated with increased risk for atherothrombotic stroke (OR, 1.80; 95% CI, 1.300-2.491). Our findings support that SNP83 of PDE4D is a genetic risk factor for atherothrombotic strokes in a Chinese population.

Vitamin k epoxide reductase: a protein involved in angiogenesis.

Vitamin K epoxide reductase (VKOR) is a newly identified protein which has been reported to convert the epoxide of vitamin K back to vitamin K, a cofactor essential for the posttranslational γ-carboxylation of several blood coagulation factors. We found that the gene is expressed ubiquitously including vascular endothelial cells, smooth muscle cells, fibroblasts and cardiomyocytes, and is overexpressed in 11 tumor tissues on microarray. Stable transfection of VKOR cDNA into tumor cell line A549 and H7402 did not promote the cell proliferation. These results promoted us to hypothesize that VKOR may also be involved in angiogenesis. To test this hypothesis, the expression of VKOR was studied in different vascular cells in developmental and pathologic heart tissues. The effects of overexpression and suppressing expression of VKOR on endothelial cell proliferation, migration, adhesion, and tubular network formation were explored. We found that VKOR expression in arteries was prominent in vascular endothelial cells and was high in the ventricular aneurysm tissue of human heart and human fetal heart. In vitro studies showed that overexpression of VKOR slightly but significantly stimulated human umbilical vein endothelial cell proliferation (by 120%), migration (by 118%), adhesion (by 117%), as well as tubular network formation. Antisense to VKOR gene inhibited the proliferation (by 67%), migration (by 64%), adhesion (by 50%), and tubular network formation. Our findings support the impact of VKOR in the process of angiogenesis; hence, the molecule may have a potential application in cardiovascular disease and cancer therapy.