Li-Yu Wang

Differential patterns of effects of age and sex on metabolic syndrome in Taiwan: Implication for the inadequate internal consistency of the current criteria

AIMS Current criteria of metabolic syndrome (MetS) give equal weight to each component and apply mostly the same cut-off values to all ages. The contribution of each component to MetS and the effects of age and sex on each component and MetS were explored. METHODS We carried out a survey on residents aged 40-74 years of the northern coastal area of Taiwan. The prevalent rates of MetS in 646 males and 961 females were 32.4% and 27.8%, respectively. Logistic regression analyses were used to assess the main and interactive effects of age and sex. The Cronbachs α coefficient was calculated as the indicator of internal consistency of MetS components. RESULTS There were significant age trends for MetS components, except for low HDL-C in both sexes and high fasting triglyceride in males. Logistic regression analyses showed that the effects of age and sex on MetS and its component were all different. The age-sex-specific Cronbachs α coefficients for MetS ranged from 0.43 to 0.61. The age trends of the coefficients in males and females were opposite. The exclusion of some components from the MetS resulted in an increase of the coefficients. CONCLUSIONS Our results indicate that the internal consistency of MetS was questionable. It seems that the currently defined MetS components of MetS did not formulate a single pathophysiological entity. Given equal weight to each component and used the same cut-off values for the subjects of all age groups in both sexes need to be reconsidered.

Associations of Cardiovascular Risk Factors with Carotid Intima-Media Thickness in Middle-Age Adults and Elders

Aims: Elevated carotid intima-media thickness (cIMT) is a preclinical phenotype of atherosclerotic diseases. There are significant sex differences in the morbidities of cardiovascular diseases and their major determinants, and we explored the sex-specific effects of cardiovascular factors on cIMT by a community-based study. Methods: We measured the cIMT and cardiovascular profiles of 1579 residents aged 40–74 years in northern Taiwan. Multivariate regression analyses were used to assess the effects and contributions of these factors on cIMT. Results: Males had significantly higher mean (± SD) of cIMT than females (0.668 ± 0.113 vs. 0.632 ± 0.100 nm, p < 0.0001). The common factors of the best-fit regression models in both sexes were age, BMI, and LDL-/HDL-C ratio; however, their contributions and effects were different. The partial coefficients of determination (r2) were 17.9, 5.8, and 4.1%, respectively, for males and were 27.8, 1.4, and 1.2%, respectively, for females. Test statistics showed that the regression coefficients of BMI and LDL-/HDL-C ratio of males were significantly higher than those of females. As compared with females, per 1.0 SD increases of BMI and LDL-/HDL-C in males resulted in 0.0971 (p = 0.030) and 0.1177 (p = 0.0087), respectively, SD increases in cIMT. There was no difference in the means of cIMT between pre- and post-menopausal women of the same age groups. Conclusions: There was a significant sex difference in cIMT. The contributions and effects of LDL-/HDL-C ratio and BMI on cIMT were more profound in males. Our findings indicate that sex-specific factors, but possibly not menstrual status-related factors, contribute to thicker cIMT.

Genetic Polymorphisms of Alcohol Metabolizing Enzymes and Alcohol Consumption are Associated With Asymptomatic Cardiac Remodeling and Subclinical Systolic Dysfunction in Large Community-Dwelling Asians

Aims Excessive consumption of alcoholic beverages is associated with cardiac remodeling and cardiomyopathy. We examined the possible association of alcohol use, common Asian genetic variants in genes involved in alcohol metabolism, and cardiac structures/functions alterations. Methods A prospective, community-dwelling survey among individuals with available complete echocardiography examined the associations of alcohol use, cardiac structure/functions, and three common alcohol metabolizing genetic variants, including aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) and cytochrome P450 (CYP) isoform 2E1 (CYP2E1). Results Among 1577 participants (mean age: 53 ± 9, 59.7% female), we observed that in subjects with more frequent weekly ethanol intake showed greater left ventricle (LV) mass, more impaired diastolic functions, and reduced global longitudinal strain (GLS), systolic (SRs) and early diastolic strain rates (SRe) (P<0.05). After propensity matching for clinical confounders (n = 330:30 for frequent users and non-users), frequent alcohol use and subjects carrying ALDH2 (A/G or A/A), ADH1B (A/A) or CYP2E1(T/C or T/T) polymorphisms were all associated with worse GLSRs and GLSRe, with combined alcohol use and any given genetic variant aggravated these associations (all P < 0.05). Finally, we observed Gene-Gene synergistic effects on LV functional decline in frequent alcohol users by using linear mixed effect model (all interaction P < 0.05). Conclusions Among East Asians, even moderate alcohol consumption can confer subclinical adverse effects on cardiac systolic functions, which was most pronounced in subjects carrying common variants in alcohol metabolizing genes. These findings challenge the notion of beneficial influences of less heavy ethanol consumption on the heart, especially among East Asians. Short summary This study evaluated the association of level of alcohol consumption and genetic variants in genes involved in alcohol metabolism with changes in cardiac function in East Asians. Even moderate alcohol use conferred subclinical adverse effects on cardiac systolic functions, which were most pronounced in subjects carrying common alcohol metabolizing genes.

BMP-2 induces angiogenesis by provoking integrin α6 expression in human endothelial progenitor cells.

Graphical abstract Figure. No Caption available. Abstract Bone morphogenetic protein‐2 (BMP‐2) is a multifunctional cytokine, capable of governing several cellular functions, including proliferation, motility, differentiation, and angiogenesis. Circulating endothelial progenitor cells (EPCs) have been shown to facilitate tissue repair, postnatal neovascularization, and tumor associated angiogenesis. Nevertheless, the impact of BMP‐2 on angiogenesis of human EPCs has largely remained a mystery. In this study, we found that BMP‐2 promoted cell migration and tube formation of EPCs in a concentration‐dependent manner, indicating BMP‐2 induced in vitro angiogenesis in human EPCs. Furthermore, BMP‐2 significantly increased microvessel formation in Matrigel plug assay, and BMP‐2 antagonist noggin prevented BMP‐2‐induced in vivo angiogenesis. Mechanistic investigations showed BMP‐2 profoundly induced the expression of Id‐1 and integrin &agr;6 as well as EPCs angiogenesis by activating PI3K/Akt and MEK/ERK signaling pathways. Moreover, knockdown of Id‐1 and integrin &agr;6 by siRNA transfection obviously attenuated BMP‐2‐indueced tube formation of EPCs. These results suggest that BMP‐2 promotes angiogenesis in human EPCs through the activation of PI3K/Akt, MEK/ERK, and Id‐1/integrin &agr;6 signaling cascades. This is the first demonstration that BMP‐2 exhibits the angiogenesis property on human EPCs. BMP‐2 might serve as the potential therapeutic target for treatment of angiogenesis‐related diseases.

Genetic profiling of young and aged endothelial progenitor cells in hypoxia

Age is a major risk factor for diseases caused by ischemic hypoxia, such as stroke and coronary artery disease. Endothelial progenitor cells (EPCs) are the major cells respond to ischemic hypoxia through angiogenesis and vascular remodeling. However, the effect of aging on EPCs and their responses to hypoxia are not well understood. CD34+ EPCs were isolated from healthy volunteers and aged by replicative senescence, which was to passage cells until their doubling time was twice as long as the original cells. Young and aged CD34+ EPCs were exposed to a hypoxic environment (1% oxygen for 48hrs) and their gene expression profiles were evaluated using gene expression array. Gene array results were confirmed using quantitative polymerase chain reaction, Western blotting, and BALB/c female athymic nude mice hindlimb ischemia model. We identified 115 differentially expressed genes in young CD34+ EPCs, 54 differentially expressed genes in aged CD34+ EPCs, and 25 common genes between normoxia and hypoxia groups. Among them, the expression of solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) increased the most by hypoxia in young cells. Gene set enrichment analysis indicated the pathways affected by aging and hypoxia most, including genes “response to oxygen levels” in young EPCs and genes involved “chondroitin sulfate metabolic process” in aged cells. Our study results indicate the key factors that contribute to the effects of aging on response to hypoxia in CD34+ EPCs. With the potential applications of EPCs in cardiovascular and other diseases, our study also provides insight on the impact of ex vivo expansion might have on EPCs.

Associations of Common Genetic Variants on IL-17 Genes and Carotid Intima-Media Thickness

Aim: Atherosclerosis is a chronic inflammatory process of the arterial wall and carotid intima-media thickness (cIMT) is regarded as its early marker. Several members of the IL-17 family are involved in pro-inflammatory functions. The specific aim of the study was to explore the relationships of common genetic variants on IL-17 genes with cIMT thickening. Methods: In the discovery stage, 146 SNPs on 11 IL-17 genes were screened for their relationships with cIMT by a case-control study that enrolled 284 and 464 subjects who had thicker and normal cIMT, respectively. Findings were replicated by an independent case-control study that enrolled 282 subjects who had thicker cIMT and 282 age-sex-matched subjects who had normal cIMT. Results: Among 134 eligible SNPs in the discovery study, only IL-17RC rs279545 was significantly correlated with cIMT (p = 6.9 × 10−5). The rs279545 and 2 nearby linked SNPs rs55847610 and rs3846167 were included in the validation study. We found that the rs279545*G, rs55847610*G, and rs3846167*C were correlated with significantly higher likelihoods of having thicker cIMT. The corresponding multivariate-adjusted ORs were 1.462 (95% CI: 1.055–2.027), 1.481 (95% CI: 1.090–2.013), and 1.589 (95% CI: 1.147–2.200), respectively. Analyses of rs279545-rs55847610 haplotypes showed that the multivariate-adjusted OR for A-A haplotype was significantly decreased (OR = 0.665, 95% CI: 0.487–0.908) and for G-G haplotype was significantly increased (OR = 1.539, 95% CI: 1.097–2.161). Conclusions: We first correlated cIMT, a preclinical clinical cardiovascular marker, with IL-17RC, the key molecule in the IL-17 signaling pathway. Our results indicated that IL-17RC may play critical role in the development of atherosclerotic diseases.

Senescence Induces Dysfunctions in Endothelial Progenitor Cells and Osteoblasts by Interfering Translational Machinery and Bioenergetic Homeostasis

Age-related bone diseases are partly caused by impaired bone integrity, which are closely related to osteoblasts’ activity and angiogenesis. Endothelial progenitor cells (EPCs) are the initiators of angiogenesis and found to have senescent-induced dysfunctions. The aim of this study is to investigate the effects of senescence in EPCs on osteogenesis and angiogenesis. Human primary EPCs and a murine osteoblast cell line (MC3T3-E1) are utilized in this study. The senescence of EPCs are induced by serial passages. When co-cultured with senescent EPCs, the osteoblasts demonstrate weakened alkaline phosphatase (ALP) activity and mineral deposition. On the other hand, osteoblast-induced migration decreases in senescent EPCs. As for the intracellular alterations of senescent EPCs, the activation of Akt/mTOR/p70S6K pathway, MnSOD and catalase are diminished. In contrast, the level of reactive oxygen species are significantly higher in senescent EPCs. Furthermore, senescent EPCs has decreased level intracellular ATP level and coupling efficiency for oxidative phosphorylation while the non-mitochondrial respiration and glycolysis are elevated. The senescence of EPCs impairs the functions of both osteoblasts and EPCs, suggesting EPCs’ role in the pathophysiology of age-related bone diseases. Targeting the alterations found in this study could be potential treatments.

J-001 A COMMUNITY-BASED ADULT COHORT STUDY ON AGING-RELATED DISORDERS: METABOLIC SYNDROME AND CAROTID ATHEROSCLEROSIS

Background It is of academic and public health relevance to explore the prevalence and determinants ofmajor aging-related disorders, especially metabolic syndrome (MetS) and cardiovascular diseases in middle-aged and elderly population. Methods We conducted a prospective community-based adult cohort study on aging-related disorders. A structured questionnaire was obtained and extensive health examination, including MetS score, biomarkers, echocardiography,carotid ultrasound, were performed and analyzed. Results A total of 731 residents, aged 40 to 74 years,were enrolled in the first wave of study during Nov 2010 to May 2011. The prevalence rates of abdominal obesity, high blood pressure, low HDL-C, high fasting triglycerides, and high fasting glucose were 32.3, 56.8, 14.5, 26.8, and 40.9%, respectively, for men and 45.9, 44.9, 15.0, 17.8, and 35.7%, for women, respectively. The prevalence rate of MetS was 26.5% for men and 25.8% for women. There were 20.9% of men withcarotid plaquesand 19.8% with an increased carotid Intima-Media Thickness (IMT). The corresponding figures for women were 12.6% and 8.3%, respectively. The proportions of the presence of carotid plaques in subjects with 0, 1∼2, and ≧3 MetSscores were 15.5, 20.1, and 29.8% (p for trend, 0.004), respectively. The corresponding figures for increased carotid IMTswere 4.9, 12.2, and 21.3% (p for trend, <0.0001), respectively. Conclusions Metabolic syndrome is prevalent in the New Taipei city, Taiwan, and high blood pressure is the most commonMetScomponent. The increase of prevalence rates of carotid atherosclerosis is perfectly in parallel to that of the MetS scores.