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Ken Ogasawara

Publications and source records attributed to Ken Ogasawara.

12 recordsLinked to original sources
PubMed2006

Human organic anion transporter 3 gene is regulated constitutively and inducibly via a cAMP-response element.

Human organic anion transporter (OAT) 3 (SLC22A8) is localized to the basolateral membranes of renal tubular epithelial cells and plays a critical role in the excretion of anionic compounds. We previously reported that interindividual variation in the OAT3 mRNA level corresponded to interindividual differences in the rate of renal excretion of cefazolin. However, there is little information available on the molecular mechanisms regulating the gene expression of OAT3. Therefore, in the present study, we examined the transcriptional regulation of human OAT3. A deletion analysis of the OAT3 promoter suggested that the region spanning -214 to -77 base pairs was essential for basal transcriptional activity. This region contained a perfectly conserved cAMP-response element (CRE), and a mutation here led to a reduction in promoter activity. Electrophoretic mobility shift assays showed that CRE-binding protein (CREB)-1 and activating transcription factor (ATF)-1 bound to CRE. The activity of the OAT3 promoter was increased through the phosphorylation of CREB-1 and ATF-1 by treatment with 8-bromo-cAMP. This paper reports the first characterization of the human OAT3 promoter and shows that CREB-1 and ATF-1 function as constitutive and inducible transcriptional regulators of the human OAT3 gene via CRE.

Base Sequence↗
PubMed2006

Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene.

BACKGROUND: Coronary artery spasm plays an important role in the pathogenesis of vasospastic angina, and contributes to the development of several acute coronary syndromes. Endothelial nitric oxide synthase (ecNOS) catalyzes the synthesis of nitric oxide, which regulates vascular tone, and may be related to coronary vasospasm. The present study investigated whether coronary spasm is related to particular polymorphisms of the ecNOS gene. METHODS AND RESULTS: Spasm provocation by serial infusions of acetylcholine was performed on 165 patients who were clinically suspected of having angina. In both study patients and healthy controls (n=400), genomic polymorphisms of the ecNOS gene were determined by using polymerase chain reaction. Quantitative luminal diameter measurements of the 3 major coronary arteries were initially obtained before and after acetylcholine injection, and then after isosorbide dinitrate injection, by using a computer-assisted analysis system. Logistic multiple regression analysis identified the a/a or a/b genotype in intron 4 of ecNOS (NOS4a: p=0.0431, odds ratio (OR) 2.43) and diabetes mellitus (p=0.0060, OR 4.88) as significant predictors of coronary spasm. In the patients with NOS4a, both the induced and spontaneous contractions were augmented. CONCLUSION: The present study results indicated that NOS4a could be a good marker for coronary artery spasm.

Acetylcholine↗
PubMed2005

Pharmacokinetic significance of renal OAT3 (SLC22A8) for anionic drug elimination in patients with mesangial proliferative glomerulonephritis.

PURPOSE: Our previous studies showed that the mRNA level of human organic anion transporter (hOAT) 3 in the kidney was correlated with the rate of elimination of an anionic antibiotic cefazolin. However, the correlation coefficient was not so high. In the present study, therefore, we enrolled more patients to examine whether additional factors were responsible for the correlation. METHODS: hOAT mRNA levels in renal biopsy specimens were quantified using the real-time polymerase chain reaction method. The elimination rates for the free fraction of cefazolin were determined in patients with various renal diseases. RESULTS: In the present study, the coefficient of correlation between the hOAT3 mRNA level and the elimination rates for the free fraction of cefazolin was not so high in the patients overall as in our previous study (r = 0.536). However, following the classification of renal diseases, a better correlation was obtained in patients with mesangial proliferative glomerulonephritis (r = 0.723). In contrast, multiple regression analyses including gender, age, and liver function did not result in any improvements in the correlation coefficients. CONCLUSIONS: These results suggest that the hOAT3 mRNA level is a significant marker of pharmacokinetics with which to predict the rate of elimination of cefazolin in patients with mesangial proliferative glomerulonephritis.

Adolescent↗
PubMed2004

A serum amyloid A and LDL complex as a new prognostic marker in stable coronary artery disease.

BACKGROUND: Although some reports have indicated that acute phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) can predict the prognosis in patients with acute coronary syndrome, the value of these markers in patients with stable coronary artery disease (CAD) still remains obscure. Therefore, our aim was to determine the prognostic value of inflammatory markers in patients with stable coronary artery disease. METHODS AND RESULTS: We conducted a prospective cohort study in 140 consecutive patients with stable coronary artery disease who had at least one coronary stenosis more than 50% in diameter seen on diagnostic coronary angiography (CAG). We determined serum levels of the SAA/LDL complex as a new marker in addition to CRP and SAA. Serum levels of the SAA/LDL complex were measured by a sandwich enzyme-linked immunosorbent assay (ELISA). End-points were defined as cardiac death, myocardial infarction, cerebral infarction, and coronary revascularization. End-point events occurred in 21 patients (2 death from myocardial infarction, 2 cerebral infarction, and 17 revascularization). Age (year) (OR = 1.14, CI: 1.05-1.25), diabetes mellitus (OR = 3.50, CI: 1.08-11.40), triglyceride (10mg/dl) (OR = 1.12, CI: 1.01-1.23) and SAA/LDL complex (10 microg/ml) (OR = 2.32, CI: 1.05-4.70) were independently related to the events. A reconstitution experiment suggested that the SAA/LDL complex is derived by oxidative interaction between SAA and lipoproteins. CONCLUSIONS: The SAA/LDL complex reflects intravascular inflammation directly and can be a new marker more sensitive than CRP or SAA for prediction of prognosis in patients with stable coronary artery disease.

Aged↗
PubMed2004

Soft plaque detected on intravascular ultrasound is the strongest predictor of in-stent restenosis: an intravascular ultrasound study.

AIMS: Although various predictors of in-stent restenosis (ISR) have been reported, the subject of parameters relating to ISR on intravascular ultrasound (IVUS) still leaves room for discussion. The aim of this study was to clarify the strongest predictors of ISR using IVUS. METHODS AND RESULTS: Ninety-two native coronary lesions undergoing single bare-metallic stent implantation were investigated retrospectively. We classified them into the ISR (n=46) and non-ISR (n=46) groups using quantitative coronary angiography. On serial IVUS studies, plaque morphology, and areas and volumes of each component in vessel were evaluated. Among all parameters, diabetes mellitus and soft plaque appearing hypoechoic on IVUS were associated with ISR. By multivariate analysis, soft plaque was the only independent predictor of ISR (p=0.0057). Compared with non-soft plaque, soft plaque had a larger plaque reduction rate (-7.1% vs. -1.6%, p=0.0613) and smaller percent plaque volume (53.0% vs. 55.5%, p=0.0273) after stenting. Conversely, soft plaque had a larger neointimal area (4.39 vs. 3.33 mm2, p=0.0437) and percent plaque area (80.5% vs. 75.1%, p=0.0503) at follow-up. CONCLUSION: Soft plaque detected on IVUS was the strongest predictor of ISR. Soft plaque was compressed more easily by stenting, however, causing more proliferation of neointima subsequently and resulted in a worse prognosis.

Aged↗
PubMed2004

[Development of blood examination method of serum amyloid A and LDL complex, and clinical application to prediction of cardiovascular event].

In recent years, it has been reported that the acute-phase proteins C-reactive protein(CRP) and serum amyloid A(SAA), the sera levels of which are elevated in inflammation, are also elevated in coronary artery disease such as acute myocardial infarction. Also, high-sensitivity CRP assay is thought to be useful in predicting the prognosis of coronary heart disease. While investigating complexes of acute-phase proteins and low-density lipoprotein(LDL), we found a complex of LDL and SAA(SAA/LDL complex). The SAA/LDL complex in blood are formed from LDL and HDL by an oxidation reaction. Therefore, we developed an ELISA using anti-human SAA antibody and anti-human apoB, and determined a new method for measuring SAA/LDL complex in sera. We evaluated SAA/LDL complex as a new marker for prediction of prognosis in addition to the ordinary markers in consecutive 140 patients with stable coronary heart disease who had at least 1 coronary artery stenosis more than 50% in diameter at the diagnostic coronary angiography. Of these 140 patients, 2 developed fatal myocardial infarction, 2 cerebral infarction, and 17 angina pectoris requiring coronary revascularization therapy during 1 year and 6 months after blood examinations. The SAA/LDL complex value in this EVENT group of 21 patients was significantly higher than that in the control group of 119 individuals. High-sensitivity CRP (hs-CRP) assay and SAA measurement showed no significant difference between the 2 groups. The SAA/LDL complex reflects intravascular inflammation directly and can be a new marker more sensitive than hs-CRP or SAA for prediction of prognosis in patients with stable coronary artery disease.

Acute-Phase Proteins↗
PubMed2003

Arterial remodeling patterns before intervention predict diffuse in-stent restenosis: an intravascular ultrasound study.

OBJECTIVES: The aim of this retrospective study was to determine the predictors of diffuse in-stent restenosis (ISR) among the lesions causing the first ISR by intravascular ultrasound (IVUS) studies. BACKGROUND: Although some predictors of diffuse ISR have been reported, parameters on IVUS relating to diffuse ISR are not well characterized. METHODS: We classified 52 ISR lesions that had undergone successful stent implantation and led to restenosis into two types--focal and diffuse ISR--using quantitative coronary angiography. Restenosis was defined as > or =50% diameter stenosis, and diffuse ISR as lesion length > or =10 mm at follow-up. The remodeling index (RI) was defined as the vessel area at the target lesion divided by that of averaged reference segments. RESULTS: There were no significant differences in patient, angiographic, and procedural characteristics between the focal (n = 25) and diffuse (n = 27) ISR groups. Baseline RI was significantly greater in the diffuse ISR group (1.03 +/- 0.18 vs. 0.88 +/- 0.24, p = 0.0159). Negative remodeling, defined as RI <0.9, was detected in 60% of the focal ISR group and in only 26% of the diffuse ISR group. By logistic regression analysis, baseline RI was the only independent predictor of diffuse ISR (p = 0.0341). Moreover, volumetric analyses revealed that lesions developing into diffuse ISR had less capacity to compensate for further plaque growth. CONCLUSIONS: Among the first ISR lesions, baseline positive remodeling was the most powerful predictor of diffuse ISR. Measuring pre-interventional arterial remodeling patterns by IVUS may be helpful to stratify lesions at higher risk.

Aged↗
PubMed2003

Genetic variations of matrix metalloproteinase-1 and -3 promoter regions and their associations with susceptibility to myocardial infarction in Japanese.

Matrix metalloproteinases (MMPs) are involved in plaque rupture, which is the main pathological cause of myocardial infarction (MI). Recently, several genetic studies have demonstrated that MMP-1 1G/2G polymorphism and MMP-3 5A/6A polymorphism modify each transcriptional activity in allele specific manners. Within this context, we conducted case-control studies to examine whether these genetic polymorphisms are associated with susceptibility to MI. Two groups comprising patients with MI (group-1 164 patients, group-2 302 patients) were compared with control group comprising 335 patients without cardiovascular diseases. The MMP-3 5A allele was more frequent in patients with MI than in the control subjects (P=0.018 MI group-1, P=0.0059 MI group-2), whereas there was no disease association for MMP-1 genotypes. Logistic regression analyses revealed that MMP-3 5A/6A polymorphism was associated with susceptibility to MI [odds ratio(OR) (95% confidential interval) 1.67 (1.02-2.74); P=0.042, MI group-1; 1.61 (1.12-2.23); P=0.0095, MI group-2]. Other important findings were that there was strong linkage disequilibrium between these polymorphisms, which are located closely on chromosome 11q.22, and that the 5A-1G haplotype was a genetic risk factor for MI (OR 1.97 P=0.0082, MI group-1 OR 1.51 P=0.017, MI group-2). Taken together, the present findings suggest that genetic variations in these MMP genes and especially their haplotype may be useful genetic markers for determining susceptibility to MI in Japanese.

Aged↗
PubMed2002

Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors.

OBJECTIVE: Heme oxygenase (HO) is important in the defense against oxidative stress and as a factor in an antiatherogenic mechanism. Compared with long (GT)(n) repeats, short (GT)(n) repeats in the human HO-1 gene promoter were shown to have higher transcriptional activity in response to oxidative stress. There is a strong link between oxidative stress and the pathogenesis of coronary artery disease (CAD). METHODS AND RESULTS: We screened the allelic frequencies of (GT)(n) repeats in the HO-1 gene promoter in 577 patients who underwent coronary angiography. Because the distribution of numbers of (GT)(n) repeats was bimodal, we divided the alleles into 2 subclasses: class S included shorter (<27) repeats, and class L included longer (> or =27) repeats. Multivariate logistic regression models including standard coronary risk factors revealed that the genotypes were significantly related to CAD status in hypercholesterolemic, diabetic patients or in smokers. In this study, the patients with shorter GT repeats were less likely to have CAD. CONCLUSIONS: Length polymorphism in the HO-1 gene promoter is related to CAD susceptibility in Japanese people who also have coronary risk factors such as hypercholesterolemia, diabetes, and smoking. HO-1 may play an antiatherogenic role in Japanese patients with these coronary risk factors.

Alleles↗
PubMed2002

Increased level of advanced oxidation protein products in patients with coronary artery disease.

Witko-Sarsat et al. previously reported that advanced oxidation protein products (AOPP), which were determined by measurements of optical density (OD) at 340 nm under acidic conditions, were present at high levels in the plasma of uremic patients. We measured AOPP in the plasma of 392 patients who underwent coronary angiography because of suspected coronary artery disease (CAD) and examined the association between plasma AOPP levels and CAD. We also collected plasma from hemodialysis patients and healthy volunteers for AOPP assay. Plasma fractionation by size-exclusion chromatography was performed to determine the weights of the molecules involved in the AOPP activity. The elution patterns obtained after plasma fractionation by size-exclusion chromatography were the similar in both CAD and hemodialysis patients, but differed from those of the healthy volunteers, whose AOPP levels were low. We also found that, the severity score of CAD obtained by the Gensini scoring system had good correlation with AOPP quartiles. Multivariable regression models revealed that the plasma AOPP level was significantly related to CAD status. This is the first report of an association between AOPP and CAD. AOPP was an independent risk factor for CAD. Oxidative stress is speculated to be associated with the pathogenesis of CAD.

Adult↗
PubMed2002

[Prevalence and clinical background of exercise-induced ventricular tachycardia during exercise testing].

OBJECTIVES: This study assessed the prevalence and clinical background of exercise-induced ventricular tachycardia during exercise testing. METHODS: Complications during exercise testing were reviewed in 25,075 consecutive patients, 14,037 men and 11,038 women, who underwent a total of 47,656 maximal treadmill or bicycle exercise tests between April 1985 and March 1999. The mean age of the patients was 53.3 +/- 8.8 (mean +/- SD) years. Non-sustained ventricular tachycardia was defined as 8 or more consecutive ventricular ectopic beats at > 100 beats/min. A total of 126 patients undergoing exercise testing to evaluate the efficacy of pharmacotherapy for ventricular tachycardia were excluded. RESULTS: The major reasons for the exercise test were chest pain (27.0%) and screening (20.3%). Twenty patients (0.08%) had exercise-induced ventricular tachycardia. Six patients had ischemic heart disease, two had cardiomyopathy, five had other cardiac diseases, and seven patients showed no clinical evidence of heart disease. The incidence of ventricular tachycardia in patients with cardiomyopathy (2/109) was higher than in other patients, but the number of patients with ventricular tachycardia was small. Ventricular tachycardia was documented at heart rates of more than 80% of predicted maximal heart rate in 12 of the 20 patients. CONCLUSIONS: These results suggest that the exercise testing can be done safely when the end-point criteria are properly applied.

Adult↗