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Masafumi Kitakaze

Publications and source records attributed to Masafumi Kitakaze.

At least 91 records · Page 5Linked to original sources
PubMed2004

Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region.

Metabolism of administered drugs is determined by expression and activity of many drug-metabolizing enzymes, such as the cytochrome P450 (P450s) family members. Pregnane X receptor (PXR) is a master transcriptional regulator of many drug/xenobiotic-metabolizing enzymes, including P450s and drug transporters. In this study, we describe the functional analysis of four naturally occurring human PXR (hPXR) variants (R98C, R148Q, R381W, and I403V) that we have recently identified. By a reporter gene assay using the CYP3A4 promoter/enhancer reporter in COS-7 or HepG2 cells, it was found that the R98C variant failed to transactivate the CYP3A4 reporter. The R381W and I403V variants also showed varying degrees of reduction in transactivation, depending on the dose of PXR activators, rifampicin, clotrimazole, and paclitaxel. The transcriptional activities of the R148Q variant were not significantly different from that of the wild-type hPXR. The electrophoretic mobility shift assay revealed that only the R98C variant lacked DNA binding. Furthermore, the cellular localization of the hPXR proteins was analyzed. All four variants as well as the wild-type hPXR localized exclusively to the nucleus, regardless of the presence or absence of rifampicin. These data suggest that the R98C, R381W, and I403V hPXR variants, especially R98C, may influence the expression of drug-metabolizing enzymes and transporters, which are transactivated by PXR.

Amino Acid Sequence↗
PubMed2004

Rationale and design of a large-scale trial using nicorandil as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Damage by a K-ATP channel opener (J-WIND-KATP).

BACKGROUND: The benefits of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) are limited by reperfusion injury. In animal models, nicorandil, a hybrid of an ATP-sensitive K(+) (KATP) channel opener and nitrates, reduces infarct size, so the Japan-Working groups of acute myocardial Infarction for the reduction of Necrotic Damage by a K-ATP channel opener (J-WIND-KATP) designed a prospective, randomized, multicenter study to evaluate whether nicorandil reduces myocardial infarct size and improves regional wall motion when used as an adjunctive therapy for AMI. METHODS AND RESULTS: Twenty-six hospitals in Japan are participating in the J-WIND-KATP study. Patients with AMI who are candidates for PCI are randomly allocated to receive either intravenous nicorandil or placebo. The primary end-points are (1) estimated infarct size and (2) left ventricular function. Single nucleotide polymorphisms (SNPs) that may be associated with the function of KATP-channel and the susceptibility of AMI to the drug will be examined. Furthermore, a data mining method will be used to design the optimal combined therapy for post-myocardial infarction (MI) patients. CONCLUSIONS: It is intended that J-WIND-KATP will provide important data on the effects of nicorandil as an adjunct to PCI for AMI and that the SNPs information that will open the field of tailor-made therapy. The optimal therapeutic drug combination will also be determined for post-MI patients.

Adult↗
PubMed2004

Rationale for the use of combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in heart failure.

BACKGROUND: The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone. METHODS AND RESULTS: One hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neurohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy, which was administered at doses standard in Japan, increased the SAS score (4.5 +/- 1.5 to 4.9 +/- 1.5, p<0.05) and decreased the plasma BNP concentration (183 +/- 163 to 135 +/- 118 pg/ml, p<0.05). In contrast, there were no changes in SAS score (4.5 +/- 1.4 to 4.6 +/- 1.4, NS) or BNP concentration (156 +/- 157 to 151 +/- 185 pg/ml, NS) in the patients receiving monotherapy. CONCLUSIONS: The results of the study demonstrate that the combination therapy, even at the standard doses for Japan, improves physical activity and plasma BNP concentration more than the monotherapy. A larger study is required to assess the effects of the combination therapy on major clinical outcomes.

Adrenergic beta-Antagonists↗
PubMed2004

Rationale and design of a large-scale trial using atrial natriuretic peptide (ANP) as an adjunct to percutaneous coronary intervention for ST-segment elevation acute myocardial infarction: Japan-Working groups of acute myocardial infarction for the reduction of Necrotic Damage by ANP (J-WIND-ANP).

BACKGROUND: The benefits of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) are limited by reperfusion injury. In animal models, atrial natriuretic peptide (ANP) reduces infarct size, so the Japan-Working groups of acute myocardial Infarction for the reduction of Necrotic Damage by ANP (J-WIND-ANP) designed a prospective, randomized, multicenter study, to evaluate whether ANP as an adjunctive therapy for AMI reduces myocardial infarct size and improves regional wall motion. METHODS AND RESULTS: Twenty hospitals in Japan will participate in the J-WIND-ANP study. Patients with AMI who are candidates for PCI are randomly allocated to receive either intravenous ANP or placebo administration. The primary end-points are (1) estimated infarct size (Sigmacreatine kinase and troponin T) and (2) left ventricular function (left ventriculograms). Single nucleotide polymorphisms (SNPs) that may be associated with the function of ANP and susceptibility of AMI will be examined. Furthermore, a data mining method will be used to design the optimal combinational therapy for post-MI patients. CONCLUSIONS: J-WIND-ANP will provide important data on the effects of ANP as an adjunct to PCI for AMI and the SNPs information will open the field of tailor-made therapy. The optimal therapeutic drug combination will also be determined for post-MI patients.

Adult↗
PubMed2004

Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2).

Thirty-three genetic variations including fourteen novel ones were found in the SLC22A2 gene from 116 Japanese individuals. The novel variations were as follows: 596C>T (MPJ6_OC2003), 602C>T (MPJ6_OC2004), IVS5+20A>G (MPJ6_OC2010), IVS5-84_-83insG (MPJ6_OC2013), IVS6+30T>C (MPJ6_OC2014), IVS6+146G>T (MPJ6_OC2016), IVS6+179G>T (MPJ6_OC2017), IVS6-16delT (MPJ6_OC2018), 1920G>A (MPJ6_OC2022), 2153G>A (MPJ6_OC2026), 2157C>T (MPJ6_OC2028), 2306T>C (MPJ6_OC2031), 2342+5T>C (the last nucleotide number of mRNA+the position in the 3'-flanking region; MPJ6_OC2032) and 2342+127T>C (MPJ6_OC2033). Six variations were located in the exons, four of which were in the 3'-untranslated region (3'-UTR) of exon 11; six were in the introns; and two were in the 3'-flanking region. The frequencies were 0.802 for IVS5-84_-83insG, 0.013 for 602C>T, 0.009 for 596C>T, and 0.004 for the other 11 variations. Among them, 596C>T and 602C>T resulted in amino acid substitutions (Thr199Ile and Thr201Met, respectively).

Amino Acid Substitution↗
PubMed2004

Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1).

Twenty genetic variations, including seven novel ones, were found in the human SLC22A1 gene, which encodes organic cation transporter 1, from 116 Japanese individuals. The novel variations were as follows: -94C>A in the 5'-untranslated region (A of the translation start codon is numbered +1 in the cDNA sequence; MPJ6_OC1001), 350C>T (MPJ6_OC1004), IVS1-35T>C (MPJ6_OC1006), 561G>A (MPJ6_OC1010), IVS6+75C>G (MPJ6_OC1014), IVS8+108A>G (MPJ6_OC1017), and 1671_1673delATG (MPJ6_OC1020). The frequencies were 0.082 for IVS1-35T>C, 0.022 for IVS6+75C>G, 0.009 for 561G>A, and 0.004 for the other 4 variations. Among them, 350C>T resulted in the amino acid substitution Pro117Leu, which is located in the large extracellular loop between transmembrane domains 1 and 2. Also, we detected the four previously reported nonsynonymous variations, 123C>G (Phe41Leu), 480C>G (Phe160Leu), 1022C>T (Pro341Leu), and 1222A>G (Met408Val) with frequencies of 0.004, 0.086, 0.168, and 0.810, respectively.

Genetic Variation↗
PubMed2004

Novel nonsynonymous single nucleotide polymorphisms in the CYP2D6 gene.

Cytochrome P450 (CYP) 2D6 is an important drug-metabolizing enzyme, and its gene is known to be highly polymorphic. Here, we report five novel nonsynonymous single nucleotide polymorphisms (SNPs), and 65 other sequence variations detected from the gene coding for cytochrome P450 (CYP) 2D6 in 254 Japanese subjects. Two of the novel nonsynonymous SNPs were associated with the *10 key SNP, C100T. Among the 65 variations, 23 were novel, including 12 SNPs in 5'-flanking, 1 in 5'-untranslated, and 10 in intronic regions. The nonsynonymous SNPs in the CYP2D6 gene were as follows: 73 C>T (Arg25Trp, exon 1), 972 C>T (Ala90Val, exon 2), 1611 T>A (Phe120Ile, exon 3), 1720 A>C (Glu156Ala, exon 3), 3172 A>C (Glu334Ala, exon 7). The SNPs, 73C>T, 972 C>T, 1611 T>A, 1720 A>C and 3172 A>C were linked with *10, *1, *10, *1 and *2, respectively.

Amino Acid Substitution↗
PubMed2004

Genetic variations of the AHR gene encoding aryl hydrocarbon receptor in a Japanese population.

Aryl hydrocarbon receptor (AhR), encoded by the AHR gene, is a transcriptional factor that induces various drug metabolizing enzymes in response to diverse endogenous and exogenous ligands. In order to identify genetic variations of the AHR gene, genomic DNA from 242 Japanese individuals was sequenced. We identified 32 single nucleotide variations, including 25 novel ones [7 were in the coding exons, 7 in the introns, 1 in the 5'-untranslated region (UTR), 5 in the 3'-UTR, 2 in the 5'-flanking region, and 3 in the 3'-flanking region] and a GGGGC repeat polymorphism (a novel microsatellite marker) in the promoter region. The novel nonsynonymous variations were 50A>C (Lys17Thr), 1202A>G (Lys401Arg), 1459A>G (Asn487Asp), and 1541T>C (Ile514Thr). The allele frequencies were 0.010 for 1459A>G (Asn487Asp) and 0.002 for the other 3 variations. Also detected in this analysis was the known nonsynonymous single nucleotide polymorphism 1661G>A (Arg554Lys) at a 0.444 frequency.

Asian People↗
PubMed2004

[Prevention and treatment of the hypersensitive organopathy--the necessity of cardiovascular protection].

In our country, cardiovascular disease, such as ischemic heart disease and apoplexy, occupies the epistasis of mortality rate. One of the causes of cardiovascular disease is arteriosclerotic change and hypertension. It is a common understanding that the prevention of the arteriosclerotic change and antihypertensive treatment are very important. Lately, it is found angiotensin-converting-enzyme inhibitor has anti-arteriosclerotic action that cannot be explained only in a blood pressure control. Reexamination of the strategy is needed in antihypertensive treatment. The close relation exists between antihypertensive treatment and cardiovascular protection. The cardiovascular protection is important in the new antihypertensive therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population.

Both UDP-glucuronosyltransferase 2B4 (UGT2B4) and UGT2B7 are expressed mainly in the human liver and have several overlapping substrates; e.g., catechol estrogens, bile acids, codeine, and carvedilol. To identify novel single nucleotide polymorphisms (SNPs) and haplotypes in a Japanese population, the enhancer/promoter regions, all the exons, and the surrounding intronic regions of UGT2B4 and UGT2B7 were sequenced from 136 Japanese individuals. We found 16 and 21 polymorphisms, including 10 and 4 novel ones in UGT2B4 and UGT2B7, respectively. The novel nonsynonymous SNPs were 1364A>G (K455R) and 1531T>C (C511R) in UGT2B4 and 1192G> A (D398N) in UGT2B7. From linkage disequilibrium analysis, several SNPs in UGT2B7 were found to be highly linked with each other. No close linkage between the SNPs in UGT2B4 and UGT2B7 was observed, indicating that each gene is located within an independent haplotype block. Thus, haplotype analysis was separately performed for the two genes. In UGT2B4, we unambiguously determined 8 haplotypes and inferred an additional 12 haplotypes using an expectation-maximization-based program. In UGT2B7, five haplotypes were unambiguously assigned and an additional eight haplotypes were inferred. The haplotype structure of UGT2B7 was more diverse than that of UGT2B4 in terms of the number of frequent SNPs. In addition, ethnic differences in the UGT2B4(*)2 and UGT2B7(*)2 haplotypes between the Japanese and the Caucasian and/or African populations were found. Our findings provide fundamental and useful information for genotyping UGT2B4 and UGT2B7 in the Japanese, and probably other populations.

Asian People↗
PubMed2004

[Usefulness of conscious sedation with midazoram during transesophageal echocardiographic examination].

OBJECTIVES: Although transesophageal echocardiography is useful to identify various cardiovascular diseases, the semi-invasive nature of the examination hampers its routine application. We investigated whether conscious sedation using a low dose of intravenous midazoram was safe and useful during the examination. METHODS: We asked 55 consecutive patients undergoing transesophageal echocardiography (44 with midazoram, mean age 59 +/- 16 years, and 11 without midazoram, mean age 62 +/- 8 years) and the examiners about the effects of midazoram using a questionnaire. RESULTS: The mean dose of midazoram was 2.2 mg (range 1-3.5 mg). All examinations were done without any adverse events. Eighty-two percent of the patients with midazoram considered the examination under conscious sedation tolerable, whereas 91% without midazoram felt it untolerable. Most examiners felt manipulation of the echo probe was easier in patients with midazoram than in those without (69% vs 27%). CONCLUSIONS: Conscious sedation with a low dose of intravenous midazoram facilitated and increased patient tolerance during transesophageal echocardiographic examination.

Aged↗
PubMed2003

Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice.

17beta-estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.

Animals↗
PubMed2003

A calcium channel blocker activates both ecto-5(')-nucleotidase and NO synthase in HUVEC.

Since amlodipine, a long-acting Ca channel blocker, increases both NO and adenosine production in canine hearts, we investigated that amlodipine activates both ecto-5(')-nucleotidase responsible for adenosine production and NO synthase (NOS) for NO production in human umbilical venous endothelial cells (HUVECs), and its cellular signaling. We measured activities of ecto-5(')-nucleotidase and NOS in HUVECs in the condition with additions of xanthine (100 microM)+xanthine oxidase (1.6 x 10(-3)U/ml) in the presence or absence of amlodipine (1 x 10(-9)-1 x 10(-6)M). Amlodipine increased both ecto-5(')-nucleotidase and NOS activities. Xanthine+xanthine oxidase deactivated both NOS and ecto-5(')-nucleotidase, and amlodipine increased both activities of NOS and ecto-5(')-nucleotidase by 117+/-33% and 48+/-6%, respectively. Amlodipine phosphorylated p38MAP kinase and that an inhibitor of p38MAP kinase inhibited the amlodipine-induced activation of both NOS and ecto-5(')-nucleotidase. Furthermore, amlodipine increased both adenosine and NO production in the canine ischemic hearts. We concluded that amlodipine activates both NOS and ecto-5(')-nucleotidase via p38MAP kinase in vitro and enhances both NO and adenosine production in vivo.

Amlodipine↗
PubMed2003

Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes.

Six novel nonsynonymous nucleotide alterations were found in the cytochrome P450 1A2 gene in a Japanese population, which resulted in the following amino acid substitutions: T83M, E168Q, F186L, S212C, G299A, and T438I. These individuals were heterozygous for the amino acid substitutions. The potential functional alterations caused by the amino acid substitutions were characterized by a cDNA-mediated expression system using Chinese hamster V79 cells. Among the six CYP1A2 variants, F186L showed the most profound and statistically significant reduction in O-deethylation of phenacetin and 7-ethoxyresorufin. Kinetic analyses performed for the ethoxyresorufin O-deethylation revealed that the Vmax of the F186L variant was approximately 5% of that of the CYP1A2 wild type, despite a 5-fold lower Km value of the variant, the consequence of which was reduced enzymatic activity toward the substrate. Thus, for the first time, phenylalanine at residue 186 is suggested to be a critical amino acid for catalytic activity.

Amino Acid Sequence↗
PubMed2003

Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model.

Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A1 receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80+/-0.18 versus 8.34+/-0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23+/-0.27 versus 10.03+/-0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dtmax were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A1 agonist N6-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A1 receptor-mediated mechanisms.

2-Chloroadenosine↗
PubMed2003

Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve.

BACKGROUND: Patients with bicuspid aortic valve (BAV) have been frequently complicated with ascending aortic dilation possibly because of hemodynamic burdens by aortic stenosis (AS) or regurgitation (AR) or congenital fragility of the aortic wall. METHODS AND RESULTS: To clarify if the aortic dilation could be prevented by aortic valve replacement (AVR) in BAV patients, we studied 13 BAV (8 AR dominant, 5 AS dominant) and 14 tricuspid aortic valve (TAV) patients (7 AR, 7 AS) by echocardiography before and after AVR (9.7+/-4.8 years). We also studied 18 BAV (11 AR, 7 AS) without AVR. Diameters of the sinuses of Valsalva, sinotubular junction and the proximal aorta were measured. The annual dilation rate was calculated by dividing changes of diameters during the follow-up period by the body surface area and the observation interval. We found that aortic dilation in BAV patients tended to be faster than that in TAV patients, although a significant difference was found only at the proximal aorta (0.18+/-0.08 versus -0.08+/-0.08 mm/(m2/year), P=0.03). BAV patients with and without AVR showed similar progressive dilation. AR dominant group showed tendency of more progressive dilation than AS dominant group in BAV, although it did not reach statistical significance. TAV patients did not show further aortic dilation after AVR. CONCLUSIONS: AVR could not prevent progressive aortic dilation in BAV. Since the aorta did not dilate in TAV, progressive aortic dilation in BAV seems mainly due to the fragility of the aortic wall rather than hemodynamic factors.

Adult↗