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Biomedical subjects

Masahiro Akishita

Publications and source records attributed to Masahiro Akishita.

At least 19 recordsLinked to original sources
PubMed2006

Signaling pathway of nitric oxide production induced by ginsenoside Rb1 in human aortic endothelial cells: a possible involvement of androgen receptor.

Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells.

Amino Acid Sequence↗
PubMed2006

Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells.

Apoptosis is essential for the initiation and progression of vascular calcification. Recently, we showed that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors (statins) have a protective effect against vascular smooth muscle cell calcification by inhibiting apoptosis, where growth arrest-specific gene 6 (Gas6) plays a pivotal role. In the present study, we clarified the downstream targets of Gas6-mediated survival signaling in inorganic phosphate (Pi)-induced apoptosis and examined the effect of statins. We found that fluvastatin and pravastatin significantly inhibited Pi-induced apoptosis and calcification in a concentration-dependent manner in human aortic smooth muscle cells (HASMC), as was found with atorvastatin previously. Gas6 and its receptor, Axl, expression were downregulated in the presence of Pi, and recombinant human Gas6 (rhGas6) significantly inhibited apoptosis and calcification in a concentration-dependent manner. During apoptosis, Pi suppressed Akt phosphorylation, which was reversed by rhGas6. Wortmannin, a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor, abolished the increase in Akt phosphorylation by rhGas6 and eliminated the inhibitory effect of rhGas6 on both Pi-induced apoptosis and calcification, suggesting that PI3K-Akt is a downstream signal of the Gas6-mediated survival pathway. Pi reduced phosphorylation of Bcl2 and Bad, and activated caspase 3, all of which were reversed by rhGas6. The inhibitory effect of statins on Pi-induced apoptosis was accompanied by restoration of the Gas6-mediated survival signal pathway: upregulation of Gas6 and Axl expression, increased phosphorylation of Akt and Bcl2, and inhibition of Bad and caspase 3 activation. These findings indicate that the Gas6-mediated survival pathway is the target of statins' effect to prevent vascular calcification.

Androstadienes↗
PubMed2006

AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling.

There are two subtypes of angiotensin (Ang) II receptors, AT1R and AT2R. It is established that clinical use of specific AT1R blocker (ARB) improves the long-term prognosis of heart failure. However, scientific basis for such effects of ARB is incompletely understood. The present study was designed to determine whether ARB inhibits the left ventricular (LV) remodeling that occurs early after myocardial infarction (MI) and whether the benefit of ARB is mediated by blockade of AT1R itself or by stimulation of AT2R resulting from AT1R blockade. MI was induced in AT2R-knockout mice and wild-type mice. Administration of valsartan, an ARB, or vehicle was started soon after the surgery and continued for two weeks. Infarction caused significant increase in end diastolic and end systolic LV dimensions, LV/body weight ratio, and myocyte cross-sectional area (MCSA) in both strains to a similar extent. Lung/body weight ratio, an index of pulmonary congestion, was also significantly increased in both strains, but the magnitude of increase was significantly larger in knockout mice. Valsartan significantly reduced LV dimensions, LV/body weight ratio, MCSA, and lung/body weight ratio in wild-type mice. In knockout mice, however, valsartan failed to inhibit the increases in LV dimensions and LV/body weight ratio. After the treatment, lung/body weight ratio in the mutant strain was significantly larger than that in the wild-type mice. Valsartan attenuates acute phase post-infarction remodeling and ameliorates heart failure, and a large part of its cardioprotective effect was mediated by AT2R.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis.

OBJECTIVE: Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells. METHODS AND RESULTS: Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01 mmol/L H(2)O(2). Edaravone treatment (10mg/kg i.p.) for 3 days suppressed endothelial apoptosis, as evaluated by chromatin staining of en face specimens at 24h, by approximately 40%. Similarly, edaravone dose-dependently inhibited H(2)O(2)-induce apoptosis of cultured endothelial cells in parallel with the inhibition of 8-isoprostane formation, 4-hydroxy-2-nonenal (4-HNE) accumulation and VCAM-1 expression. Next, apolipoprotein-E knockout mice were fed a high-cholesterol diet for 4 weeks with edaravone (10mg/kg i.p.) or vehicle treatment. Edaravone treatment decreased atherosclerotic lesions in the aortic sinus (0.18+/-0.01 to 0.09+/-0.01 mm(2), P<0.001) and descending aorta (5.09+/-0.86 to 1.75+/-0.41 mm(2), P<0.05), as evaluated by oil red O staining without influence on plasma lipid concentrations or blood pressure. Dihydroethidium labeling and cytochrome c reduction assay showed that superoxide anions in the aorta were suppressed by edaravone. Also, plasma 8-isoprostane concentrations and aortic nitrotyrosine, 4-HNE and VCAM-1 contents were decreased by edaravone treatment. CONCLUSIONS: These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy.

Aldehydes↗
PubMed2006

Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway.

Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K-dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 micromol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which was increased by Pi in a concentration-dependent manner, and not by inhibiting sodium-dependent phosphate cotransporter (NPC) activity, another mechanism regulating HASMC calcification. Furthermore, the antiapoptotic effect of statins was dependent on restoration of Gas6, whose expression was downregulated by Pi. Restoration of Gas6 mRNA by statins was mediated by mRNA stabilization, and not by an increase in transcriptional activity. Suppression of Gas6 using small interfering RNA and the Axl-extracellular domain abolished the preventive effect of statins on Pi-induced apoptosis and calcification. These data demonstrate that statins protected HASMC from Pi-induced calcification by inhibiting apoptosis via restoration of the Gas6-Axl pathway.

Aorta↗
PubMed2006

[An elderly case with nontuberculous mycobacteria acompanied by unilateral massive pleural effusion following the video-assisted thoracic surgery (VATS) for lung cancer].

We report an elderly case with nontuberculous mycobacteria (NTM). Four years after left lung upper lobectomy due to lung cancer by the video-assisted thoracic surgery (VATS), an 81 year-old patient complained of general fatigue and appetite loss. Although he did not exhibit fever or respiratory tract symptoms, a Chest X ray film revealed unilateral massive pleural effusion in the left lung. NTM (Runyon classification type II) was grown in the sputum culture. Neither mycobacterium tuberculosis DNA nor M. avium-intracellulare complex DNA was detected by polymerase chain reaction. The pleural effusion adenosine deaminase (ADA) activity was 127.6U/l. NTM was considered as the most probable diagnosis. After admission his condition and appetite improved. Chest computed tomography (CT) scan showed reduction of left pleural effusion, but another pulmonary nodule lesions were sustained. Although the abnormal findings on chest CT did not totally resolve, we did not prescribe antituberculosis drugs, based on the comprehensive assessment of his NTM disease state. The pathogenesis and diagnosis of HTM in elderly cases was discussed.

Aged, 80 and over↗
PubMed2005

Angiotensin converting enzyme inhibitor attenuates oxidative stress-induced endothelial cell apoptosis via p38 MAP kinase inhibition.

BACKGROUND: The effects of angiotensin converting enzyme (ACE) inhibitors on oxidative stress-induced apoptosis of endothelial cells and the intracellular signaling were investigated. METHODS: Cultured endothelial cells derived from a bovine carotid artery were treated with H2O2 or TNF-alpha to induce apoptosis. Apoptosis was evaluated by DNA fragmentation and cell viability, p38 MAP kinase activity by Western blotting, and oxidative stress by formation of 8-isoprostane. The effects of ACE inhibitors were examined by adding them into the medium throughout the experiments. RESULTS: Apoptosis was attenuated by ACE inhibitors, temocapril and captopril, in a dose-dependent manner (1-100 micromol/l). H2O2 (0.2 mmol/l for 1.5 h) or TNF-alpha (10 ng/ml for 72 h) treatment stimulated the activities of p38 MAP kinase. Temocapril and captopril decreased the activity of p38 MAP kinase as well as 8-isoprostane formation induced by H2O2. A p38 MAP kinase inhibitor, SB203580, partially inhibited the effect of temocapril on apoptosis. CONCLUSIONS: These results suggest that ACE inhibitors protect endothelial cells from oxidative stress-induced apoptosis, and that p38 MAP kinase plays a critical role in the process.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Renin-angiotensin system modulates oxidative stress-induced endothelial cell apoptosis in rats.

The role of the renin-angiotensin system in oxidative stress-induced apoptosis of endothelial cells (ECs) was investigated using a rat model and cultured ECs. EC apoptosis was induced by 5-minute intra-arterial treatment of a rat carotid artery with 0.01 mmol/L H2O2 and was evaluated at 24 hours by chromatin staining of en face specimens with Hoechst 33342. Although activity of angiotensin-converting enzyme in arterial homogenates was not increased, administration of an angiotensin-converting enzyme inhibitor temocapril for 3 days before H2O2 treatment inhibited EC apoptosis, followed by reduced neointimal formation 2 weeks later. Also, an angiotensin II type 1 (AT1) receptor blocker (olmesartan) inhibited EC apoptosis, whereas angiotensin II administration accelerated apoptosis independently of blood pressure. Next, cultured ECs derived from a bovine carotid artery were treated with H2O2 to induce apoptosis, as evaluated by DNA fragmentation. Combination of angiotensin II and H2O2 dose-dependently increased EC apoptosis and 8-isoprostane formation, a marker of oxidative stress. Conversely, temocapril and olmesartan reduced apoptosis and 8-isoprostane formation induced by H2O2, suggesting that endogenous angiotensin II interacts with H2O2 to elevate oxidative stress levels and EC apoptosis. Neither an AT2 receptor blocker, PD123319, affected H2O2-induced apoptosis, nor a NO synthase inhibitor, NG-nitro-L-arginine methyl ester, influenced the effect of temocapril on apoptosis in cell culture experiments. These results suggest that AT1 receptor signaling augments EC apoptosis in the process of oxidative stress-induced vascular injury.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Impact of blood pressure variability on cardiovascular events in elderly patients with hypertension.

Blood pressure variability is one of the characteristic features of hypertension in the elderly. However, its clinical significance remains to be determined. We therefore examined the impact of blood pressure variability on the development of cardiovascular events in elderly hypertensive patients. A total of 106 consecutive hypertensive patients aged more than 60 years old (mean age, 73.9 +/- 8.1 years old; male, 54%), all of whom underwent 24-h ambulatory blood pressure monitoring, were followed up (median, 34 months; range, 3-60 months). During the follow-up period, 39 cardiovascular events were observed, including 14 cases of cerebral infarction and 7 cases of acute myocardial infarction. The coefficient of variation (CV) of 24-h systolic blood pressure (SBP) values was used as an index of blood pressure variability. The patients showed a mean CV value of 10.6%, and were divided into two groups according to this mean value as a cut-off point: a high CV group (n = 46) and a low CV group (n = 60). Although baseline clinical characteristics were similar in the two groups, Kaplan-Meier plots for event-free survival revealed that the rate of cardiovascular events was significantly higher in high CV group than in low CV group (p < 0.05). Cox's proportional hazards analysis showed that increased blood pressure variability (a high CV value of 24-h SBP) was an independent predictive variable for cardiovascular events. The CV value of daytime SBP and the SD value of both 24-h SBP and daytime SBP also had positive correlations with the onset of cardiovascular events. These results suggest that increased blood pressure variability may be an independent risk factor for cardiovascular events in elderly hypertensive patients.

Aged↗
PubMed2005

[Characteristics and limitation of portable bedside swallowing test in elderly with dementia: comparison between the repetitive saliva swallowing test and the simple swallowing provocation test].

Several bedside portable swallowing tests have been advocated for screening for dysphagia. However, the clinical usefulness and limitation of these tests have not been examined in elderly patients with dementia. We performed the repetitive saliva swallowing test (RSST) and the simple swallowing provocation test (SSPT) in 37 elderly inpatients (81.8 +/- 1.2 years old). Simultaneously, cognitive and verbal communication ability were assessed by the Hasegawa Dementia Scale revised version (HDSR) and the Mini-Communication Test (MCT). RSST was completed only in 22 patients (59%), whereas SSPT was successfully completed in all cases. Scores of HDSR and MCT were significantly lower in patients who were unable to cooperate with RSST compared to successful examinees (HDSR: 7 +/- 1 vs 15 +/- 3, p < 0.0; MCT: 47 +/- 8 vs 81 +/- 5, p < 0.01). Dysphagia was detected in 14 patients (64%) by RSST and 5 (14%) by SSPT. Patients with dysphagia showed significantly lower cognitive function (p < 0.05) and verbal communication ability (p < 0.05). In conclusion, RSST is more sensitive to detect dysphagia in elderly patients; however, compliance with RSST is strongly influenced by the patient's cognitive function and verbal communication ability. Comprehensive geriatric assessment will help to choose an alternative test for dysphagia such as SSPT which is more specific test for aspiration pneumonia.

Aged↗
PubMed2005

[Development of a portable fall risk index for elderly people living in the community].

AIM: To develop a portable risk index for falls. METHODS: Risk factors were chosen from previously established factors then we added several environmental factors to the risk index; previous falls in the last 12 month, trippig or stumbling, inability to ascend or descend stairs without help, decreased walking speed, inability to cross a road within the green signal interval, inability to walk 1km without a break, inability to stand on one leg for 5 seconds (eyes open), using a cane, inability to wring out a towel, dizziness or faintness, stooped or rounded back, knee joint pain, visual disturbance, hearing disturbance, cognitive decline, fear of falling, receiving 5 or more prescribed drugs, sensation of darkness at home, obstacles inside, barrier on the carpet or floor, using steps daily at home, steep slopes around home. SUBJECTS: The questionnaire sheet was completed by 2,439 community-dwelling elderly subjects (76.3 +/- 7.4 years old). The frequency of each items of fall risk index was compared between fallers (history of fall within one year) and non-fallers. Multiple regression analysis was performed to identify independent risk factors for previous falls. RESULTS: Except barrier, step use and steep slope around home, all items in the fall risk index were more frequent in fallers. Multivariate analysis revealed that tripping or stumbling, inability to cross a road within the green signal interval, dizziness or faintness, obstacles inside, inability to wring out a towel, cane use and knee joint pain were independent risk factors for previous falls. These 7 selected items were further analyzed as predictors. The maximum sum of sensitivity and specificity was reached at the cut-off point of 2/3 (sensitivity 0.65, specificity 0.72) by receiver operating curve. CONCLUSION: Portable fall risk index is useful for clinical settings to identify high-risk subjects.

Accidental Falls↗
PubMed2004

Inhibitory effect of low-dose estrogen on neointimal formation after balloon injury of rat carotid artery.

The current regimens of hormone replacement therapy for postmenopausal women, estrogen combined with progestogen, have failed to show beneficial effects for the prevention of atherosclerotic disease. Although the relatively higher dose of estrogen contained in those regimens exerted adverse effects, there are few data examining a lower dose of estrogen in an atherosclerosis model. Therefore, we investigated experimentally whether lower doses of estrogen could inhibit neointimal formation after balloon injury of the rat carotid artery. Ten-week-old Wistar rats were subjected to ovariectomy or sham-operation (n=7). Four days after ovariectomy, rats were implanted with an osmotic mini-pump containing 17-beta estradiol (0.2, 1, 2, 10 and 20 microg/kg/day; n=6, 4, 8, 6 and 5, respectively) or placebo (n=10). After 3 days of hormone therapy, balloon injury was performed in the left common carotid artery. Neointimal formation was histologically evaluated 2 weeks after injury. Cross-sectional intimal area and the ratio of intimal area to medial area were dose-dependently reduced by estrogen replacement compared with those in ovariectomized rats without estrogen replacement. The effects of estrogen replacement were identical to those of an angiotensin II type 1 receptor blocker, candesartan. Interestingly, the effect was significant even in rats receiving lower doses of estrogen, in which plasma estradiol concentrations were not increased and the hyperplastic response of the uterus was minimal. These results suggest the efficacy of low-dose estrogen therapy for the protection of atherosclerosis.

Animals↗
PubMed2004

Caveolin-1, Id3a and two LIM protein genes are upregulated by estrogen in vascular smooth muscle cells.

Estrogen has diverse effects on the vasculature, such as vasodilation, endothelial growth and inhibition of vascular smooth muscle cell (VSMC) proliferation and migration. However, little is known about the genes that are regulated by estrogen in the vascular wall. Wistar rats were ovariectomized or sham-operated (Sham group), and 2 weeks after the operation, were subjected to subcutaneous implantation of placebo pellets (OVX + V group) or estradiol pellets (OVX + E group). Endothelium-denuded aortic tissue was examined 2 weeks after implantation. By applying high-density oligonucleotide microarray analysis, the expression of approximately 7000 genes was analyzed. Among the genes with different expression levels between the OVX + E group and the OVX + V group, those that have been reported to be expressed in the vasculature or muscle tissue, were chosen. Finally, four genes, caveolin-1, two LIM proteins (enigma and SmLIM) and Id3a, were identified. Microarray as well as real-time polymerase chain reaction showed that the expression levels of these genes were significantly higher in the OVX + E group than in the OVX + V group. To clarify whether estrogen directly upregulates these genes in the vascular wall, Northern blot analysis was performed using cultured rat VSMC. Addition of 100 nmol/L estradiol for 24 hours increased the mRNA levels of all four genes. Although the precise mechanism remains unclear, regulation of these genes by estrogen might contribute to its effect on VSMC.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Interrelationship between non-invasive measurements of atherosclerosis: flow-mediated dilation of brachial artery, carotid intima-media thickness and pulse wave velocity.

Flow-mediated dilation (FMD) of the brachial artery, carotid intima-media thickness (IMT) and pulse wave velocity (PWV) have been shown to be good surrogate markers of clinical atherosclerosis. We determined the interrelation between these measurements, and examined whether their combination would be of clinical significance. One hundred and thirty-five consecutive subjects (79 women/56 men) were enrolled, including 110 patients with risk factors for atherosclerosis, and 33 patients with atherosclerotic disease such as coronary heart disease, stroke or arteriosclerosis obliterans. IMT and plaque formation of the carotid artery and FMD of the brachial artery were assessed using ultrasonography. Brachial-ankle PWV (baPWV) was measured using an automated device (form ABI/PWV, Colin). Age, FMD, IMT and PWV were significantly correlated with each other. Multivariate analysis revealed an independent correlation between the parameters except for FMD, and all four parameters were independently correlated with each other in subjects <70 years. Next, we classified the subjects by tertile according to the values of FMD, IMT and PWV. Each of the worst tertiles was associated with a higher prevalence of atherosclerotic disease and carotid plaques compared to the other tertiles. Moreover, subjects with the worst tertiles of all three measurements had a markedly higher prevalence of atherosclerotic disease and carotid plaques. These results suggest that FMD, IMT and PWV are related to each other, but the combination of these measurements will be of stronger clinical relevance.

Aged↗