Tomoko Monguchi

Serum Trans-Fatty Acid Concentration Is Elevated in Young Patients With Coronary Artery Disease in Japan

BACKGROUND Adverse effects of dietary intake of trans-fatty acids (TFA) on the incidence of coronary artery disease (CAD) are well recognized in Western countries. The risk of TFA, however, has not been well clarified in Japan. We investigated the association of serum TFA concentration with serum lipid profile, coronary risk factors, and prevalence of CAD. METHODSANDRESULTS A total of 902 patients, who were hospitalized at Kobe University Hospital from July 2008 to March 2012 and gave written informed consent, were enrolled in this study. Among them, 463 patients had CAD, and 318 patients had metabolic syndrome (MetS). Serum TFA, elaidic acid (trans-9-C18:1) and linolelaidic acid (trans-9, 12-C18:2), were measured on gas chromatography/mass spectrometry. Serum TFA level had a positive correlation with body mass index, waist circumference, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B48, and an inverse correlation with age and high-density lipoprotein cholesterol. Fasting serum TFA, by age quartile in the young generation with CAD and/or MetS, was higher than that in patients without CAD and/or MetS. On multivariate logistic regression, TFA was identified as a CAD risk after adjustment for classical risk factors. CONCLUSIONS Serum TFA concentration was elevated in young patients with CAD and/or MetS. Diet-derived TFA may cause a serious health problem, particularly in the young generation in Japan.

Fasting serum concentration of apolipoprotein B48 represents residual risks in patients with new-onset and chronic coronary artery disease.

BACKGROUND To identify new therapeutic targets for coronary artery disease (CAD), we investigated whether fasting serum concentration of apolipoprotein (apo) B48 could be a marker for CAD. METHODS Patients with CAD were divided into those with new-onset CAD [i.e., those receiving percutaneous coronary intervention (PCI) for the first time] and those with chronic CAD (i.e., those receiving follow-up coronary angiography). Fasting serum biochemical analyses were performed on admission and 6 months after the PCI. RESULTS On admission, serum LDL-C concentrations in patients with chronic CAD (n=138), presumably receiving statin treatment, were lower than in patients with new-onset CAD (n=50, p<0.02) or without CAD (n=71, p<0.001). Nevertheless, apoB48 was higher in CAD patients than in those without CAD (p<0.001). After adjusting for classic cardiovascular risk factors, multivariate logistic regression analyses showed apoB48 to be an independent predictor of coronary risk in new-onset or chronic CAD, irrespective of the LDL-C levels. Moreover, apoB48 was markedly increased during the follow-up period in CAD patients having new lesion progression after the prior PCI. CONCLUSION Fasting serum apoB48 concentration could be a marker of new onset as well as chronic CAD, and predict new lesion progression in secondary prevention.

Trans-fatty acid promotes thrombus formation in mice by aggravating antithrombogenic endothelial functions via Toll-like receptors

SCOPE Since excessive intake of trans-fatty acid (TFA) increases the risk of myocardial infarction, we investigated the effects of TFA on thrombus formation using animal and cell culture experiments. METHODS AND RESULTS C57BL/6 mice were fed a diet containing TFA or cis-fatty acid (5% each of total calories) or a chow diet for 4 weeks, and thrombus formation was induced in the carotid artery by He-Ne laser irradiation. The high-TFA diet significantly promoted thrombus formation in the carotid artery compared to the chow or cis-fatty acid diet. TFA activated the inflammatory signaling pathway in cultured endothelial cells and in mice; aortic gene expression levels of antithrombogenic molecules, including thrombomodulin and tissue factor pathway inhibitor, were decreased, and the expression levels of prothrombogenic molecules were increased in TFA-treated mice. TFA markedly upregulated the prothrombogenic molecules and downregulated the antithrombogenic molecules in endothelial cells. In addition, TFA induced phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor-κB. The TFA-activated signal pathways and prothrombogenic phenotypic changes of endothelial cells were inhibited by genetic or pharmacological inactivation of Toll-like receptors 2 and 4. CONCLUSION TFA aggravates the antithrombogenic phenotypes of vascular endothelial cells via Toll-like receptors and promotes thrombus formation in mice.

Excessive intake of trans fatty acid accelerates atherosclerosis through promoting inflammation and oxidative stress in a mouse model of hyperlipidemia

BACKGROUND Epidemiological studies have demonstrated that trans fatty acids (TFAs) are a risk for coronary artery disease. However, the precise mechanism underlying the proatherogenic effect of TFA has not been completely elucidated. To obtain better understanding of the impact of TFA on vascular diseases, this study investigated the effect of TFA on oxidative stress using a mouse model of atherosclerosis. METHODS Low-density lipoprotein (LDL) receptor knockout mice were fed with diet containing 0.5% cholesterol (control), 0.5% cholesterol+5% elaidic acids (Trans group), and 0.5% cholesterol+5% oleic acids (Cis group) for 8 weeks. Atherosclerotic lesion and oxidative stress in aortic wall were evaluated. In vitro experiments using smooth muscle cells were performed to corroborate in vivo findings. RESULTS The atherosclerotic lesion area was significantly larger in Trans group than that in control or Cis group. Lipoprotein fractionation was similar among groups, while plasma oxidized LDL level and superoxide production in the vessel wall were markedly increased in Trans group. Elaidic acids were accumulated in a variety of tissues including liver and adipose tissue, which was associated with the high level of inflammatory cytokines in these tissues and plasma. Aortic wall from Trans group showed augmented expression of reactive oxygen species and NAPDH oxidase (p22phox) in smooth muscle cells. In vitro experiments confirmed that elaidic acids upregulated expression of NADPH oxidase and inflammatory cytokines in cultured smooth muscle cells. CONCLUSION Excessive intake of TFA contributes to the progression of atherosclerosis by evoking inflammation and oxidative stress in mice.

Targeted Disruption of JCAD (Junctional Protein Associated With Coronary Artery Disease)/KIAA1462, a Coronary Artery Disease–Associated Gene Product, Inhibits Angiogenic Processes In Vitro and In Vivo

Objective— Recent genome-wide association studies newly identified the human KIAA1462 gene as a new locus for coronary artery disease. However, the function of the gene product, named JCAD (junctional protein associated with coronary artery disease), is unknown. Because JCAD is expressed at cell–cell junctions in endothelial cells, we hypothesized and tested whether JCAD regulates angiogenic processes in vitro and in vivo. Approach and Results— Cell culture experiments revealed impaired angiogenic ability (proliferation, migration, and cord formation) by the knockdown of JCAD with siRNA (P<0.05 versus control siRNA). We have generated mice lacking JCAD (mKIAA1462−/−) by gene-targeted deletion of JCAD to address in vivo angiogenic function. mKIAA1462−/− mice did not show morphological differences in development of retinal vasculature. Ex vivo aortic ring model demonstrated impaired neovascularization in aorta from mKIAA1462−/− mice than control wild-type mice (P<0.05). Tumor growth was assessed by monitoring tumor volume after the subcutaneous injection of melanoma, LLC (Lewis lung carcinoma), and E0771 cells into the mice. mKIAA1462−/− mice exhibited significantly smaller tumor volume compared with wild-type mice (P<0.001). Histological assessment of the tumor exhibited less smooth muscle actin–positive neovascularization determined by CD31-positive vascular structure in tumor of mKIAA1462−/− mice than wild-type mice, indicating that knockdown of JCAD inhibited the vascular maturation in pathological angiogenic process. Conclusions— These in vitro and in vivo studies suggest that JCAD has a redundant functional role in physiological angiogenesis but serves a pivotal role in pathological angiogenic process after birth.

PITAVASTATIN INCREASES HDL PARTICLES WITH PRESERVED ANTI–ATHEROSCLEROTIC PROPERTIES IN DYSLIPIDEMIC PATIENTS

It has been recently postulated that not only the quantity but also quality of HDL play an important role in the progression and regression of atherosclerosis. Pitavastatin is a unique statin that possesses both LDL–decreasing and HDL–increasing effects. To clarify whether the HDL increased by