Ryuji Toh

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (35)148.53 Total impact

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    ABSTRACT: Granular leukocyte-derived myeloperoxidase (MPO) promotes oxidation of lipoproteins, while paraoxonase 1 (PON1) has antioxidant properties for high-density lipoprotein (HDL). We evaluated their effects on coronary risk stratification and function of lipoproteins. A total 158 patients who had previously undergone percutaneous coronary intervention and who had been hospitalized for coronary re-angiography were enrolled. Coronary lesions (restenosis or de novo lesion) were observed in 84 patients but not associated with conventional lipid profile. In contrast, serum MPO levels and PON1 activities were significantly associated with the prevalence of coronary lesions. The high MPO/PON1 ratio, when cutoff values were set at 1.59, was independently correlated with restenosis (odds ratio 6.4, 95% CI 2.2-19.3, P = 0.001) and de novo lesions (odds ratio 3.5, 95% CI 1.3-9.4, P = 0.014). We isolated HDL from patients with high or low MPO/PON1 ratio, and compared anti-inflammatory properties of HDL. Human umbilical vein endothelial cells were stimulated with inflammatory cytokine, and the expression of vascular cell adhesion molecule-1 (VCAM-1) was evaluated. HDL isolated from patients with low serum MPO/PON1 ratio inhibited VCAM-1 expression significantly greater than that with high MPO/PON1 ratio. We also demonstrated that the cholesterol efflux capacity of apolipoprotein B-depleted serum from patients with high MPO/PON1 ratio was significantly decreased than that with low MPO/PON1 ratio. MPO/PON1 ratio could be a useful marker for secondary prevention of coronary artery disease through modulation of HDL function.
    Atherosclerosis 03/2014; 234(2):288-294. · 3.71 Impact Factor
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    ABSTRACT: Objective Granular leukocyte-derived myeloperoxidase (MPO) promotes oxidation of lipoproteins, while paraoxonase 1 (PON1) has antioxidant properties for high-density lipoprotein (HDL). We evaluated their effects on coronary risk stratification and function of lipoproteins. Methods and results A total 158 patients who had previously undergone percutaneous coronary intervention and who had been hospitalized for coronary re-angiography were enrolled. Coronary lesions (restenosis or de novo lesion) were observed in 84 patients but not associated with conventional lipid profile. In contrast, serum MPO levels and PON1 activities were significantly associated with the prevalence of coronary lesions. The high MPO/PON1 ratio, when cutoff values were set at 1.59, was independently correlated with restenosis (odds ratio 6.4, 95% CI 2.2–19.3, P = 0.001) and de novo lesions (odds ratio 3.5, 95% CI 1.3–9.4, P = 0.014). We isolated HDL from patients with high or low MPO/PON1 ratio, and compared anti-inflammatory properties of HDL. Human umbilical vein endothelial cells were stimulated with inflammatory cytokine, and the expression of vascular cell adhesion molecule-1 (VCAM-1) was evaluated. HDL isolated from patients with low serum MPO/PON1 ratio inhibited VCAM-1 expression significantly greater than that with high MPO/PON1 ratio. We also demonstrated that the cholesterol efflux capacity of apolipoprotein B-depleted serum from patients with high MPO/PON1 ratio was significantly decreased than that with low MPO/PON1 ratio. Conclusions MPO/PON1 ratio could be a useful marker for secondary prevention of coronary artery disease through modulation of HDL function.
    Atherosclerosis 01/2014; 234(2):288–294. · 3.71 Impact Factor
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    ABSTRACT: Aim: Endothelial lipase(EL) is a determinant of plasma levels of high-density lipoprotein cholesterol(HDL-C). However, little is known about the impact of EL activity on plasma lipid profile. We aimed to establish a new method to evaluate EL-specific phospholipase activity in humans. Methods: Plasma samples were obtained from 115 patients with coronary artery disease(CAD) and 154 patients without CAD. Plasma EL protein was immunoprecipitated using an anti-EL monoclonal antibody after plasma non-specific immunoglobulins were removed by incubation with ProteinA. The phospholipase activity of the immunoprecipitated samples was measured using a fluorogenic phospholipase substrate, Bis-BODIPY FL C11-PC. Results: The EL-specific phospholipase assay revealed that plasma EL activity was inversely correlated with HDL-C levels(R=-0.3088, p<0.0001). In addition, the EL activity was associated with cigarette smoking. Furthermore, EL activity in CAD patients was significantly higher than that in nonCAD patients. Concomitantly, the HDL-C level in CAD patients were significantly lower than that in non-CAD patients. Conclusion: We have established a method for human plasma EL-specific phospholipase activity by combination of EL immunoprecipitation and a fluorogenic phospholipid substrate. Plasma EL activity was associated with not only plasma HDL-C levels but also the risks for CAD.
    Journal of atherosclerosis and thrombosis 12/2013; · 2.93 Impact Factor
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    ABSTRACT: Significance: Arterial blood vessels functionally and structurally adapt to altering hemodynamic forces in order to accommodate changing needs and to provide stress homeostasis. This ability is achieved at the cellular level by converting mechanical stimulation into biochemical signals (i.e., mechanotransduction). Whereas physiological mechanical stress helps to maintain vascular structure and function, pathologic or aberrant stress may impair cellular mechano-signaling, and initiate or augment cellular processes which drive disease. Recent advances: Reactive oxygen species (ROS) may represent an intriguing class of mechanically- regulated second messengers. Chronically enhanced ROS-generation may be induced by adverse mechanical stresses, and is associated with a multitude of vascular diseases. Although a causal relationship has clearly been demonstrated in large numbers of animal studies, an effective ROS-modulating therapy still remains to be established by clinical studies. Critical issues and Future directions: This review article focuses on the role of various mechanical forces (in the form of laminar shear stress, oscillatory shear stress or cyclic stretch) as modulators of ROS- driven signaling, and their subsequent effects on vascular biology and homeostasis, as well as on specific diseases such as arteriosclerosis, hypertension and abdominal aortic aneurysms. Specifically, it highlights the significance of the various NADPH oxidase (NOX) isoforms as critical ROS generators in the vasculature. Directed targeting of defined components in the complex network of ROS (mechano)signaling may represent a key for successful translation of experimental findings into clinical practice.
    Antioxidants & Redox Signaling 07/2013; · 8.20 Impact Factor
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    ABSTRACT: The contribution of abdominal aortic aneurysm (AAA) disease to human morbidity and mortality has increased in the aging, industrialized world. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of the diseased aorta. This work aims to develop novel diagnostic and therapeutic strategies to limit AAA expansion and, ultimately, rupture. Contributions from multiple research groups have uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining aortic vascular homeostasis. Recently, novel small noncoding RNAs, called microRNAs, have been identified as important transcriptional and post-transcriptional inhibitors of gene expression. MicroRNAs are thought to "fine tune" the translational output of their target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. With the discovery that microRNAs act as powerful regulators in the context of a wide variety of diseases, it is only logical that microRNAs be thoroughly explored as potential therapeutic entities. This current review summarizes interesting findings regarding the intriguing roles and benefits of microRNA expression modulation during AAA initiation and propagation. These studies utilize disease-relevant murine models, as well as human tissue from patients undergoing OPEN ACCESS
    International Journal of Molecular Sciences 07/2013; 14:14374-14394. · 2.46 Impact Factor
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    ABSTRACT: Aim: Although statins increase the plasma concentration of high-density lipoprotein cholesterol (HDL-C), it has not been elucidated whether the increased HDL particles possess normal antiatherosclerotic properties. Pitavastatin functions to increase the plasma HDL-C level and decrease the low-density lipoprotein cholesterol (LDL-C) level. In the present study, we sought to examine the qualitative changes in HDL during pitavastatin treatment.Methods: A total of 30 patients with dyslipidemia were treated with 2 mg of pitavastatin for four weeks. The cholesterol efflux capacity and activities of the antioxidative enzymes paraoxonase-1 (PON-1) and platelet-activating factor acetylhydrolase (PAF-AH) were evaluated using polyethethylene glycol-treated HDL fractions before and after pitavastatin treatment.Results: Pitavastatin treatment decreased the serum LDL-C level by 39% and increased the serum HDL-C level by 9% (p<0.05). In addition, pitavastatin increased the phospholipid content of HDL by 7.8% (p<0.05). The pitavastatin-induced increase in the HDL-C level coincided with an increase in the cholesterol efflux capacity of the isolated HDL fraction of 8.6% (p<0.05). The post-pitavastatin treatment activity of HDL-associated PON-1 (paraoxonase and arylesterase) was increased by 9% (p<0.05) and 11% (p<0.05), respectively, while the HDL-associated PAF-AH activity was not affected by pitavastatin.Conclusions: In addition to its LDL-C-lowering effects, pitavastatin elevates the HDL-C level and enhances the cholesterol efflux capacity and antioxidative properties of HDL. Pitavastatin therefore increases the amount of functional HDL without attenuating HDL quality.
    Journal of atherosclerosis and thrombosis 06/2013; · 2.93 Impact Factor
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    ABSTRACT: Lipoprotein lipase has been considered as the only enzyme capable of generating lipid-derived fatty acids for cardiac energy. Endothelial lipase is another member of the triglyceride lipase family and hydrolyzes high-density lipoproteins. Although endothelial lipase is expressed in the heart, its function remains unclear. We assessed the role of endothelial lipase in the genesis of heart failure. Pressure overload-induced cardiac hypertrophy was generated in endothelial lipase-/- and wild-type mice by ascending aortic banding. Endothelial lipase expression in cardiac tissues was markedly elevated in the early phase of cardiac hypertrophy in wild-type mice, whereas lipoprotein lipase expression was significantly reduced. Endothelial lipase-/- mice showed more severe systolic dysfunction with left-ventricular dilatation compared with wild-type mice in response to pressure overload. The expression of mitochondrial fatty acid oxidation-related genes, such as carnitine palmitoyltransferase-1 and medium-chain acyl coenzyme A dehydrogenase, was significantly lower in the heart of endothelial lipase-/- mice than in wild-type mice. Also, endothelial lipase-/- mice had lower myocardial adenosine triphosphate levels than wild-type mice after aortic banding. In cultured cardiomyocytes, endothelial lipase was upregulated by inflammatory stimuli, whereas lipoprotein lipase was downregulated. Endothelial lipase-overexpression in cardiomyocytes resulted in an upregulation of fatty acid oxidation-related enzymes and intracellular adenosine triphosphate accumulation in the presence of high-density lipoprotein. Endothelial lipase may act as an alternative candidate to provide fatty acids to the heart and regulate cardiac function. This effect seemed relevant particularly in the diseased heart, where lipoprotein lipase action is downregulated.
    Hypertension 03/2013; · 6.87 Impact Factor
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    ABSTRACT: 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 6months 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.
    Clinica chimica acta; international journal of clinical chemistry 02/2013; · 2.54 Impact Factor
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    ABSTRACT: OBJECTIVE: Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear. METHODS AND RESULTS: Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly attributable in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model. CONCLUSIONS: These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2012; · 6.34 Impact Factor
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    ABSTRACT: : Although pulmonary arterial hypertension (PAH) and chronic heart failure (CHF) lead to exercise limitation, their pathophysiology is different. Our objective was to evaluate, using right heart catheterization and cardiopulmonary exercise testing, the difference in hemodynamic parameters and exercise capacity between PAH and CHF, which have the same subjective symptoms. : We studied 20 PAH (mean pulmonary artery pressure: 36 ± 10 mmHg, all . 25 mmHg) and 20 CHF (ejection fraction: 35 ± 10%, all < 40%) patients who underwent both cardiopulmonary exercise testing and right heart catheterization. All patients were in New York Heart Association functional class II or III. : Peak oxygen uptake (VO2) was lower for PAH patients than for CHF patients (11.7 ± 3.2 mL·kg·min vs 14.5 ± 4.6 mL·kg·min, P = .03), while the slope of ventilation to carbon dioxide production ratio (VE/VCO2) was higher for PAH patients than for CHF patients (41.0 ± 12.7 vs 28.0 ± 9.0, P = .001), despite the similarity in their New York Heart Association functional class. Peak VO2 and VE/VCO2 correlated with cardiac index for both groups. An important finding was that peak VO2 correlated with pulmonary vascular resistance for PAH patients (r = 20.46, P = .04) but not for CHF patients (r = 0.33, P = .15). Furthermore, peak VO2 correlated with pulmonary capillary wedge pressure for CHF patients (r = 20.47, P = .03) but not for PAH patients (r = 0.17, P = .47), while the VE/VCO2 slope correlated with pulmonary capillary wedge pressure (r = 0.67, P = .002) but not with pulmonary vascular resistance (r = 0.12, P = .63) for CHF patients. : Peak VO2 and VE/VCO2 slope were worse for PAH patients than for CHF patients despite the similar subjective symptoms. This difference might be explained by an altered hemodynamic status.
    Journal of cardiopulmonary rehabilitation and prevention 11/2012; 32(6):379-85. · 1.59 Impact Factor
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    ABSTRACT: Aim: Endothelial lipase (EL) regulates plasma high-density lipoprotein-cholesterol (HDL-C) levels by promoting HDL catabolism. However, it remains unknown whether the inhibition of EL has beneficial effects on the genesis of vascular diseases. Here, we investigated the role of EL on vascular remodeling in mice.Methods: Vascular remodeling was developed by ligation of the left common carotid artery and neointimal lesions were histologically compared between EL-knockout (ELKO), EL-transgenic (ELTg), and wild-type (WT) mice. HDL was isolated from these mice, and effects of the HDL on cell growth and Erk activation were evaluated in vitro using cultured vascular smooth muscle cells.Results: Plasma HDL-C levels were 62% higher in ELKO and 13% lower in ELTg than in WT mice, after the carotid ligation. The size of neointimal lesion was significantly larger in ELTg and smaller in ELKO than in WT mice. Vascular expression of adhesion molecules was lower in ELKO and higher in ELTg compared with WT mice. Moreover, oxidative stress was attenuated in ELKO mice. HDL isolated from ELKO, ELTg, and WT mice inhibited expression of intercellular adhesion molecule-1, angiotensin II-induced activation of Erk, and growth of cultured vascular smooth muscle cells, whereas EL expression itself did not affect cell migration or growth.Conclusion: EL expression modulates vascular remodeling as well as plasma HDL-C levels. EL inactivation may increase HDL particles that can inhibit smooth muscle cell growth and migration.
    Journal of atherosclerosis and thrombosis 09/2012; · 2.93 Impact Factor
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    ABSTRACT: The objective of this study is to examine the effects of thiazide diuretics, plus medium-dose losartan versus maximal-dose angiotensin II receptor blockers (ARBs) on blood pressure (BP) in Japanese patients with uncontrolled hypertension despite the use of medium-dose ARBs. Hypertensive patients in whom BP was inadequately controlled by treatment with medium-dose ARBs alone or with calcium-channel blockers were enrolled. Patients were randomly assigned to a fixed-dose combination of 50 mg per day losartan and 12.5 mg per day hydrochlorothiazide (HCTZ; n=98), or to a maximal dose of current ARBs (n=95). The reduction in office BP from baseline was significantly larger in the losartan/HCTZ group than in the maximal-dose ARB group (systolic BP -22.7±13.7 vs. -11.7±13.0 mm Hg, diastolic BP -9.6±10.9 vs. -4.5±11.0 mm Hg; P<0.01, respectively). The proportion of patients in whom the therapeutic target BP was achieved was greater in the losartan/HCTZ group than in the maximal-dose ARB group (59.2 vs. 26.3%; P<0.001). Both early-morning and evening BP were controlled more effectively over 1 year of treatment in the losartan/HCTZ group than in the maximal-dose ARB group (the mean BP difference between the groups, early-morning: 5.6 mm Hg (P=0.001), evening: 3.8 mm Hg (P=0.049)). Adverse changes in serum potassium and uric acid were observed in the losartan/HCTZ group; however, both changes were very slight, and the values were still within the normal range. The concomitant usage of losartan and HCTZ had no influence on glucose metabolism and lipid profiles. Declines in plasma N-terminal pro-brain natriuretic peptide levels and urinary albumin excretion were observed in the losartan/HCTZ group, but not in the maximal-dose ARB group. Switching from medium-dose ARBs to losartan plus HCTZ reduced both office and home BP efficiently in patients with uncontrolled hypertension.Hypertension Research advance online publication, 12 July 2012; doi:10.1038/hr.2012.110.
    Hypertension Research 07/2012; · 2.79 Impact Factor
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    ABSTRACT: Background: Cytochrome P450 (CYP) 2C19 polymorphism is associated with reduced responsiveness to clopidogrel and poor clinical outcome after drug-eluting stent (DES) implantation, but its contribution to lesion outcome after DES implantation is unclear. Methods and Results: The study included 160 Japanese patients who received clopidogrel and underwent DES implantation with follow-up angiography. Patients were divided into 3 groups by CYP2C19 polymorphism: extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). The incidence of major adverse cardiac events (MACE) and target lesion revascularization (TLR) were compared among the 3 groups. Optical coherence tomography (OCT) was performed for 120 patients to evaluate the incidence of intra-stent thrombi. Of the 160 patients, the proportion of EM, IM, and PM was 37.5%, 48.1%, and 14.4%, respectively. The incidence of TLR and MACE was more frequent in IM and PM than EM (TLR: 18.2% and 26.1% vs. 3.3%, P=0.008, MACE: 22.1% and 30.4% vs. 5.0%, P=0.005). Among the 120 patients who underwent follow-up OCT, intra-stent thrombi were more frequently detected in IM and PM than in EM (45.6% and 63.2% vs. 20.5%, P=0.005). The incidence of TLR was significantly higher in patients with than in those without intra-stent thrombi (27.7% vs. 6.8%, P=0.003). Conclusions: CYP2C19 loss-of-function polymorphism might be associated with the incidence of MACE and TLR in association with intra-stent thrombi.  (Circ J 2012; 76: 2348-2355).
    Circulation Journal 07/2012; 76(10):2348-55. · 3.58 Impact Factor
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    ABSTRACT: Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.
    Science translational medicine 02/2012; 4(122):122ra22. · 10.76 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.
    The Journal of clinical investigation 02/2012; 122(2):497-506. · 15.39 Impact Factor
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2011; 57(14).
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    ABSTRACT: Background: The cytochrome P450 (CYP) 2C19*2 polymorphism is associated with reduced responsiveness to clopidogrel and poor clinical outcome after stent implantation. Despite the high frequency of this polymorphism in Japanese patients, its contribution to cardiac events and stent thrombi after drug-eluting stent (DES) implantation is not clear in this population. Methods and Results: One hundred Japanese patients received clopidogrel and underwent follow-up optical coherence tomography (OCT) after DES implantation. The patients were divided into 2 groups: those with at least one CYP2C19*2 allele (*2 carriers) and non-carriers. The incidence of stent thrombosis and major adverse cardiac events (MACE; ie, death, myocardial infarction, and target vessel revascularization) was compared between the 2 groups. In addition, OCT was used to evaluate the incidence of intra-stent thrombus, defined as a mass protruding into the lumen with significant attenuation. Of the 100 patients, 42 were *2 carriers. No remarkable differences in the baseline characteristics were noted. Although MACE did not differ significantly between the 2 groups, a subclinical intra-stent thrombus was detected more frequently in *2 carriers than in non-carriers (52.3% vs. 15.5%, P=0.0002). Multivariate logistic regression analysis showed that the presence of the CYP2C19*2 polymorphism was the only independent predictive factor for intra-stent thrombus (P=0.00006). Conclusions: From these results it is suggested that CYP2C19*2 polymorphism is associated with subclinical thrombus formation among Japanese patients receiving clopidogrel. (Circ J 2011; 75: 99-105).
    Circulation Journal 12/2010; 75(1):99-105. · 3.58 Impact Factor
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    ABSTRACT: Previous studies have shown that targeted deletion of endothelial lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL(-/-) and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL(-/-) and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL(-/-) mice. In contrast, the lipopolysaccharide-neutralizing capacity of HDL was significantly higher in EL(-/-) mice than that in WT mice. To evaluate the anti-inflammatory actions of HDL in vivo, lipopolysaccharide-induced systemic inflammation was generated in these mice. EL(-/-) mice showed higher survival rate and lower expression of inflammatory markers than WT mice. Intravenous administration of HDL isolated from EL(-/-) mice significantly improved the mortality after lipopolysaccharide injection in WT mice. In conclusion, targeted disruption of EL increased HDL particles with preserved anti-inflammatory and anti-atherosclerotic functions. Thus, EL inhibition would be a useful strategy to raise 'good' cholesterol in the plasma.
    The Journal of Lipid Research 10/2010; 52(1):57-67. · 4.39 Impact Factor
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    ABSTRACT: Endothelial cell-selective adhesion molecule (ESAM) is a new member of the immunoglobulin superfamily, which is expressed in vascular endothelial cells. Previous studies have demonstrated that ESAM regulates angiogenesis, endothelial permeability, and leukocyte transmigration. However, little is known concerning the role of ESAM in atherosclerosis. In this study, we assessed the effects of ESAM inactivation on atherosclerosis in mice. ESAM-/- mice were bred with apoE-/- mice to generate double knockout mice, and the aortic lesion size of apoE-/- and ESAM-/-apoE-/- mice was compared histologically. Although plasma cholesterol levels were higher in ESAM-/-apoE-/- mice, the lesion size was markedly smaller than in apoE-/- mice. ESAM-/-apoE-/- mice exhibited a decrease in the number of vasa vasorum and macrophages in the vessel wall. In vitro adhesion assays showed that THP-1 cells, which did not express ESAM, bound to the ESAM-coated culture plates, suggesting that ESAM may interact with heterophilic ligand(s) on monocytes. Moreover, downregulation of ESAM by siRNA in the endothelial monolayer diminished transendothelial migration of THP-1 cells. In conclusion, ESAM inactivation can reduce susceptibility to atherosclerosis by inhibiting plaque neovascularization and macrophage infiltration into the atheroma.
    Microvascular Research 09/2010; 80(2):179-87. · 2.93 Impact Factor
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    ABSTRACT: In addition to their cholesterol-lowering effect, statins increase high-density lipoprotein cholesterol (HDL-C) levels. Endothelial lipase (EL) is a regulator of plasma HDL-C levels. In the present study, the effects of statins on EL expression were investigated. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin suppressed basal and cytokine-treated EL expression in endothelial cells. Concomitant treatment with mevalonate or geranylgeranyl pyrophosphate completely reversed the inhibitory effect of pitavastatin, suggesting that geranylgeranylated proteins are involved in the inhibition of EL expression by statins. Inhibition of RhoA activity by overexpression of a dominant-negative mutant of RhoA or a Rho kinase inhibitor decreased EL levels. Pitavastatin reduced phospholipase activities of endothelial cells, and concomitant treatment with mevalonate reversed its inhibitory effect. Pitavastatin reduced RhoA activity and EL expression in mouse tissues. Furthermore, plasma EL concentrations in human subjects were measured by enzyme-linked immunosorbent assays. Plasma EL levels were negatively associated with plasma HDL levels in 237 patients with cardiovascular diseases, and pitavastatin treatment reduced plasma EL levels and increased HDL-C levels in 48 patients with hypercholesterolaemia. These findings suggest that statins can reduce EL expression in vitro and in vivo via inhibition of RhoA activity. The inhibition of EL expression in the vessel wall may contribute to the anti-atherogenic effects of statins.
    Cardiovascular research 07/2010; 87(2):385-93. · 5.81 Impact Factor

Publication Stats

297 Citations
148.53 Total Impact Points

Institutions

  • 2013
    • Karolinska Institutet
      Solna, Stockholm, Sweden
    • Stanford Medicine
      • Division of Cardiovascular Medicine
      Stanford, CA, United States
  • 2012
    • Stanford University
      • Division of Cardiovascular Medicine
      Stanford, CA, United States