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Biomedical subjects

Masafumi Kitakaze

Publications and source records attributed to Masafumi Kitakaze.

At least 55 records · Page 3Linked to original sources
PubMed2005

Smad1 protects cardiomyocytes from ischemia-reperfusion injury.

BACKGROUND: We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury. METHODS AND RESULTS: The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the alpha-myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene-positive mouse hearts. To examine whether Smad1 prevents injury of cardiomyocytes in vivo, we subjected Smad1TG and age-matched wild-type mice (WT) to I/R injury induced by 1 hour of ligation of the left coronary artery and 1 hour of reperfusion. TUNEL and DNA ladder analyses showed that Smad1TG had significantly smaller myocardial infarctions and fewer apoptotic deaths of cardiomyocytes than did WT. Interestingly, increased expression of Bcl-xL and beta-catenin was more remarkable whereas caspase3 was less activated in Smad1TG heart than in that of WT. CONCLUSIONS: These findings suggest that the Smad1 signaling pathway plays a role in cardioprotection against I/R injury.

Animals↗
PubMed2005

Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model.

BACKGROUND: Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown. METHODS AND RESULTS: We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null (MEKK1-/-) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1-/- arteries compared with WT arteries (28+/-8 versus 65+/-17 microm2, P<0.05). There were no differences in the ratios of proliferating cell nuclear antigen (PCNA)-positive cells to total cells within the arterial wall between WT and MEKK1-/- arteries. Proliferation capacity also did not differ between WT and MEKK1-/- cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1-/- arteries. Three different migration assays revealed that migration and invasion of MEKK1-/- AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1-/- AoSMCs. The number of MEKK1-/- AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1-/- arteries. CONCLUSIONS: MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.

Animals↗
PubMed2005

Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice.

OBJECTIVE: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling. METHODS: Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C57 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression. RESULTS: Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l-arginine methylester (l-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89+/-0.48 mg/g in treated mice vs. 8.76+/-0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39+/-0.93 mg/g vs. 10.53+/-0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice. CONCLUSION: These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway.

Animals↗
PubMed2005

Amlodipine ameliorates myocardial hypertrophy by inhibiting EGFR phosphorylation.

The effects of long-acting calcium channel blockers on pressure overload-induced cardiac hypertrophy have been little studied in experimental animals and the underlying mechanisms are not fully understood. We previously reported that cardiomyocyte hypertrophy could be induced via phosphorylation of the epidermal growth factor receptor (EGFR). In this study, we investigated whether amlodipine attenuates cardiac hypertrophy by inhibiting EGFR phosphorylation. We found that amlodipine dose-dependently inhibited epinephrine-induced protein synthesis and EGFR phosphorylation in cultured neonatal rat cardiomyocytes. Our in vivo study revealed that amlodipine could ameliorate myocardial hypertrophy induced by transverse aortic constriction (TAC) in C57/B6 mice. One week after TAC, amlodipine treatment (3 mg/kg/day) significantly reduced the heart-to-body weight ratio (6.04 +/- 0.16 mg/g vs. 6.90 +/- 0.45 mg/g in untreated TAC mice, P < 0.01). These results indicate that amlodipine ameliorates cardiomyocyte hypertrophy via inhibition of EGFR phosphorylation.

Amlodipine↗
PubMed2005

Prevention of left ventricular remodeling by long-term corticosteroid therapy in patients with cardiac sarcoidosis.

Forty-three patients with cardiac sarcoidosis were studied echocardiographically before and after (mean follow-up 88 months) steroid therapy to determine the effectiveness of corticosteroids to prevent left ventricular (LV) remodeling and improve LV contractility. In patients with initial LV ejection fractions (LVEFs) >or=55%, long-term steroid therapy showed preventive effects for LV remodeling and LV function. Patients with LVEF <54% showed significant reductions of LV volumes and LVEF improvement. However, in patients with LVEFs <30%, steroid therapy resulted in neither LV volume reductions nor improved LVEFs. In the early or middle stage of the disease, steroid therapy may be protective or therapeutic in preventing LV remodeling and preserving LV function. However, it may not be as effective in the late stage.

Adult↗
PubMed2005

Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts.

Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size (high dose (1,000 IU/kg): 7.7 +/- 1.6%, low dose (100 IU/kg): 22.1 +/- 2.4%, control: 40.0 +/- 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion (high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction.

Animals↗
PubMed2005

A calcium channel blocker amlodipine increases coronary blood flow via both adenosine- and NO-dependent mechanisms in ischemic hearts.

Amlodipine reduces oxidative stress that decreases NO and adenosine release. This study was undertaken to examine whether amlodipine mediates coronary vasodilation and improves myocardial metabolism and contractility in ischemic hearts via either adenosine- or NO-dependent mechanisms. In open-chest dogs, amlodipine (2 mug kg per min) was infused at the minimum dose that caused maximal coronary vasodilation. The perfusion pressure was reduced in the left anterior descending coronary artery so that coronary blood flow (CBF) decreased by 50%. Amlodipine increased the difference of the adenosine level (VAD (Ado): 119+/-14 to 281+/-46 nM) and the nitrate+nitrite level (VAD (NOx): 7.8+/-1.3 to 16.1+/-1.1 muM) between coronary venous and coronary arterial blood, and also increased CBF (50+/-3 to 69+/-6 ml/100 g/min). These changes were partially reversed by either 8-sulfophenyeltheophylline (8SPT) or l(omega)-nitro arginine methyl ester (l-NAME), and were completely blocked by both 8SPT and l-NAME. The reduction of CBF increased VAD (8-iso-prostaglandin F(2alpha)), and this increase was reduced by amlodipine (10.8+/-1.1 to 5.0+/-0.5 pg/ml). In addition, pretreatment with superoxide dismutase mimicked the coronary effects of amlodipine and blunted the response to amlodipine administration. Amlodipine-induced coronary vasodilation via both adenosine- and NO-dependent mechanisms. Adenosine and NO may interact in ischemic hearts to mediate coronary vasodilation by amlodipine.

Adenosine↗
PubMed2005

Pharmacokinetic characteristics of amiodarone in long-term oral therapy in Japanese population.

To evaluate the pharmacokinetic properties and an optimum dose schedule of amiodarone in long-term oral therapy, serum concentrations of amiodarone and its metabolite, desethylamiodarone, were monitored from 345 Japanese inpatients who received amiodarone therapy for a variety of cardiac arrhythmias. Serum amiodarone and desethylamiodarone concentrations were determined by high performance liquid chromatography system. It was observed that the amiodarone and desethylamiodarone concentrations gradually increased with time. The frequency distribution in the amiodarone clearance of 245 subjects, who received fixed maintenance amiodarone therapy for at least 6 months, was nearly a unimodal one. The variation in the ratio of desetylamiodarone to amiodarone concentration in serum was very small. Although no differences in age, dose, dose duration, amiodarone or desethyamiodarone concentration or ratio were observed between men and women: however, the mean amiodarone clearance of women was significantly higer than that of men. The laboratory data were mostly within normal values and no significant relations were observed between serum amiodarone concentration and clinical laboratory data. These results suggest that the individual variation in pharmacokinetics of amiodarone is comparatively small, which might be sufficient to decide that the maintenance dose was the same one (200 mg/d) in long-term oral amiodarone therapy.

Administration, Oral↗
PubMed2005

Cilostazol reduces target lesion revascularization after percutaneous transluminal angioplasty in the femoropopliteal artery.

BACKGROUND: Although percutaneous transluminal angioplasty (PTA) is being widely used for the treatment of stenosis of peripheral arteries, the high in-stent restenosis rate (50-60%) in the femoropopliteal artery still remains an unsolved issue. Cilostazol is a unique antiplatelet drug that has vasodilatory effects and inhibits smooth muscle cell proliferation. METHODS AND RESULTS: A total of 141 consecutive patients scheduled for PTA in the femoropopliteal artery between September 1999 and April 2004 were retrospectively analyzed for the use of cilostazol. Target lesion revascularization (TLR) was defined as repeated PTA in patients who had a recurrence of symptoms with diameter stenosis >50% by angiography. Patient and lesion characteristics were similar between the cilostazol (+) and cilostazol (-) groups. Use of other medications was similar between the groups, except for ticlopidine, which was more frequently used in the cilostazol (-) than in the cilostazol (+) group (15% vs 61%, p<0.01). TLR was significantly reduced in the cilostazol (+) group (12% [8/68] vs 32% [23/73], p<0.01). CONCLUSIONS: Although this study was retrospective and nonrandomized, the results suggest that cilostazol reduces TLR after PTA in the femoropopliteal artery.

Aged↗
PubMed2005

Cardiac tumor as an initial manifestation of acquired immunodeficiency syndrome.

A cardiac tumor was the first manifestation of acquired immunodeficiency syndrome (AIDS) in a female patient in a state of severe immunodeficiency caused by human immunodeficiency virus (HIV) infection. The extensive cardiac and extracardiac involvement shown by various imaging modalities, including echocardiography and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), suggested that she was in the critical stage of non-Hodgkin's lymphoma (NHL). AIDS was treated by highly active-antiretroviral therapy and the NHL was treated by a combination of rituximab-cyclophosphamide-vincristine-doxorubicine-predonisolone. After 6 cycles of chemotherapy, she was in complete remission. Her cardiac tumor dramatically reduced in size and FDG-PET showed no positive uptake on whole body imaging. Generally, an AIDS-related cardiac tumor tends to be diagnosed at the late stage of the disease because of its nonspecific clinical findings, resulting in an extremely poor prognosis. In the present case, the cardiac tumor was detected by echocardiography and treated with appropriate chemotherapy. Early diagnosis and prompt treatment may improve a patient's prognosis.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Genetic variations and haplotypes of UGT1A4 in a Japanese population.

Nineteen genetic variations, including 11 novel ones, were found in exon 1 and its flanking region of the UDP-glucuronosyltransferase (UGT) 1A4 gene from 256 Japanese subjects, consisting of 60 healthy volunteers, 88 cancer patients and 108 arrhythmic patients. These variations include -217T>G and -36G>A in the 5'-flanking region, 30G>A (P10P), 127delA (43fsX22; frame-shift from codon 43 resulting in the termination at the 22nd codon, codon 65), 175delG (59fsX6), 271C>T (R91C), 325A>G (R109G), and 357T>C (N119N) in exon 1, and IVS1+1G>T, IVS1+98A>G and IVS1+101G>T in the following intron. Among them, 127delA and 175delG can confer early termination of translation, resulting in an immature protein that probably lacks enzymatic activity. Variation IVS1+1G>T is located at a splice donor site and thus may lead to aberrant splicing. Since we did not find any significant differences in the frequencies of all the variations among the three subject groups, the data were analyzed as one group. The allele frequencies of the novel variations were 0.006 for IVS1+101G>T, 0.004 for 30G>A (P10P) and 357T>C (N119N), and 0.002 for the 8 other variations. In addition, the two known nonsynonymous single nucleotide polymorphisms (SNPs), 31C>T (R11W) and 142T>G (L48V), were found at 0.012 and 0.129 frequencies, respectively. The SNP 70C>A (P24T), mostly linked with 142T>G (L48V) in German Caucasians, was not detected in this study. Sixteen haplotypes were identified or inferred, and some haplotypes were confirmed by cloning and sequencing. It was shown that most of 142T>G (L48V) was linked with -219C>T, -163G>A, 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T, comprising haplotype *3a; haplotype *4a harbors 31C>T (R11W); 127delA (43fsX22) and 142T>G (L48V) were linked (haplotype *5a); 175delG (59fsX6) was linked with 325A>G (R109G) (*6a haplotype); and -219C>T, -163G>A, 142T>G (L48V), 271C>T (R91C), 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T comprised haplotype *7a. Our results provide fundamental and useful information for genotyping UGT1A4 in the Japanese and probably Asian populations.

Arrhythmias, Cardiac↗
PubMed2005

Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population.

In order to identify genetic polymorphisms and haplotype frequencies of CYP1A2 in a Japanese population, the enhancer and promoter regions, all the exons with their surrounding introns, and intron 1 were sequenced from genomic DNA from 250 Japanese subjects. Thirty-three polymorphisms were found, including 13 novel ones: 2 in the enhancer region, 5 in the exons, and 6 in the introns. The most common single nucleotide polymorphism (SNP) was -163C>A (CYP1A2*1F allele) with a 0.628 frequency. In addition to six previously reported non-synonymous SNPs, three novel ones, 125C>G (P42R, CYP1A2*15 allele, MPJ6_1A2032), 1130G>A (R377Q, *16 allele, MPJ6_1A2033), and 1367G>A (R456H, *8 allele, MPJ6_1A2019), were found with frequencies of 0.002, 0.002, and 0.004, respectively. No polymorphism was found in the known nuclear transcriptional factor-binding sites in the enhancer region. Based on linkage disequilibrium analysis, the CYP1A2 gene was analyzed as one haplotype block. Using the 33 detected polymorphisms, 14 haplotypes were unambiguously identified, and 17 haplotypes were inferred by aid of an expectation-maximization-based program. Among them, the second major haplotype CYP1A2*1L is composed of -3860G>A (*1C allele), -2467delT (*1D allele), and -163C>A (*1F allele). Network analysis suggested that relatively rare haplotypes were derived from three major haplotypes, *1A, *1M, and *1N in most cases. Our findings provide fundamental and useful information for genotyping CYP1A2 in the Japanese, and probably Asian populations.

Adrenergic beta-Antagonists↗
PubMed2005

Stereoselective effect of amiodarone on the pharmacokinetics of racemic carvedilol.

We investigated whether there was a stereoselective effect of amiodarone on the pharmacokinetics of carvedilol. Among a series of 106 inpatients with heart failure, 52 received carvedilol monotherapy (carvedilol group) and 54 received carvedilol plus amiodarone (carvedilol+amiodarone group). The serum carvedilol concentration administered/dose ratio was compared between the two groups based on HPLC measurement of the serum levels of carvedilol, amiodarone, and desethylamiodarone. In 6 patients from the carvedilol group, serum carvedilol levels were compared before and after coadministration of amiodarone. There was no significant between-group difference of the serum concentration to dose (C/D ratio) for the R-enantiomer carvedilol, however, the C/D ratio for the S-enantiomer and the serum S-carvedilol to R-carvedilol (S/R) ratio were both significantly lower in the carvedilol group than in the carvedilol+amiodarone group(47.8+/-56.7 versus 95.3+/-105 ng/mg/kg, P=0.0048 and 0.460+/-0.207 versus 0.879+/-0.377 ng/mg/kg, P<0.001), respectively. Furthermore, the mean S-carvedilol concentration over 14 days of coadministration with amiodarone was higher than that before coadministration (6.54+/-1.73 ng/mL versus 3.03+/-0.670 ng/mL, P<0.001). These results suggest that metabolism of S-carvedilol was markedly inhibited by coadministration of amiodarone.

Adrenergic beta-Antagonists↗
PubMed2005

Genetic polymorphisms of UGT1A6 in a Japanese population.

Thirteen single nucleotide polymorphisms (SNPs), including 6 novel ones, were found in exon 1 and its flanking region of UDP-glucuronosyltransferase (UGT) 1A6 from 195 Japanese subjects. Several novel SNPs were identified, including 269G>A (R90H), 279A>G (S93S), and 308C>A (S103X) in exon 1, and IVS1+109C>T, IVS1+120A>G, and IVS1+142C>T in the intron downstream of exon 1. Among these SNPs, 308C>A confers termination of translation at codon 103, resulting in the production of an immature protein that probably lacks enzymatic activity. The allele frequencies were 0.003 for all the 6 SNPs. In addition, the 3 known nonsynonymous SNPs were detected: 19T>G (S7A), 541A>G (T181A), and 552A>C (R184S) with frequencies of 0.226, 0.218, and 0.226, respectively. High linkage disequilibrium was observed among 19T>G (S7A), 315A>G (L105L), 541A>G (T181A), 552A>C (R184S), and IVS1+130G>T, as reported in Caucasian and African-American populations. Then, 11 haplotypes in UGT1A6 were estimated. The novel nonsynonymous variant, 269A or 308A, was shown to be located on the same DNA strand together with 19G, 315G, 541G, 552C, and IVS1+130T. Our results provide fundamental and useful information for genotyping UGT1A6 in the Japanese, and probably Asian populations.

Asian People↗
PubMed2005

[A role of magnesium: magnesium in the therapy for cardiovascular diseases].

Magnesium (Mg(2+)) is well known as a natural Ca channel blocker, and has various actions to benefit for the cardiovascular system. The point of action is culminated to (1) Ca antagonism, (2) beta-adrenoceptors blocking action, and (3) anti-platelet action. Because Mg(2+) is one of physiology materials, more ideal effect can be expected than Mg(2+). On the other hand, in the new large-scale clinical trial of acute myocardial infarction (MAGIC), Mg(2+) was not able to show the expected outcomes although Mg(2+) is an important co-factor of 5'-nucleotidase activity which is a production enzyme of adenosine and may show cardioprotective effect through adenosine production increase. Therefore, we must say that we need further investigation on the role of Mg(2+) on the cardiovascular protection.

Cardiovascular Diseases↗
PubMed2004

Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure.

BACKGROUND: Ghrelin is a novel growth hormone-releasing peptide that also induces vasodilation, inhibits sympathetic nerve activity, and stimulates feeding through growth hormone-independent mechanisms. We investigated the effects of ghrelin on left ventricular (LV) function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF). METHODS AND RESULTS: Human synthetic ghrelin (2 microg/kg twice a day) was intravenously administered to 10 patients with CHF for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, and blood sampling were performed before and after ghrelin therapy. A single administration of ghrelin elicited a marked increase in serum GH (25-fold). Three-week administration of ghrelin resulted in a significant decrease in plasma norepinephrine (1132+/-188 to 655+/-134 pg/mL; P<0.001). Ghrelin increased LV ejection fraction (27+/-2% to 31+/-2%; P<0.05) in association with an increase in LV mass and a decrease in LV end-systolic volume. Treatment with ghrelin increased peak workload and peak oxygen consumption during exercise. Ghrelin improved muscle wasting, as indicated by increases in muscle strength and lean body mass. These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy. CONCLUSIONS: These preliminary results suggest that repeated administration of ghrelin improves LV function, exercise capacity, and muscle wasting in patients with CHF.

Aged↗