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Biomedical subjects

Koichi Kozaki

Publications and source records attributed to Koichi Kozaki.

At least 19 recordsLinked to original sources
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

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

Single center experience of 39 patients with preoperative portal vein thrombosis among 404 adult living donor liver transplantations.

Living donor liver transplantation (LDLT) for patients with portal vein thrombosis (PVT) involves technical difficulty. The aim of this research was to analyze their preoperative diagnosis of PVT, operative procedures, and postoperative courses of patients with preoperative PVT. Thirty-nine patients of 404 adult patients (9.7%) undergoing LDLT in our hospital from 1996 June to 2004 December had PVT at their transplantation. Twenty-nine patients had intractable ascites, 21 had gastrointestinal bleeding, and 18 had encephalopathy. The thrombus was located in the portal trunk in 23, in the portal trunk and superior mesenteric vein (SMV) in 7, and developed into the SMV and the splenic vein in 8. The occlusive grade was partial in 29, and complete in 10 patients. The thrombus was removed by a simple technique, and eversion and/or incision technique, or total removal of the portal vein (PV). The PV was reconstructed with the thrombectomized native PV, with an interposed vein graft, or porto-caval hemitransposition. Advanced PVT had a significant impact on blood loss and hospital mortality. Three out of 10 patients with residual PVT required radiological and/or surgical intervention after transplantation. In conclusion, thorough planning is essential for a successful LDLT outcome for patients with preexisting PVT.

Adolescent↗
PubMed2006

Long-term outcomes of 600 living donor liver transplants for pediatric patients at a single center.

This report concerns the long-term outcome of living donor liver transplantation (LDLT) for pediatric patients at a single center. Between June 1990 and December 2003, a total of 600 LDLTs, including 568 primary transplantations and 32 retransplantations, were performed for pediatric patients, who were immunosuppressed with FK506 and low-dose corticosteroids. Patient survival at 1, 5, and 10 years were 84.6%, 82.4%, and 77.2%, respectively, and the corresponding findings for graft survivals were 84.1%, 80.9%, and 74.5%. Multivariate analysis demonstrated that fulminant hepatic failure (FHF), a graft vs. body weight (GBWR) ratio of <0.8, and ABO-incompatible transplants were independently associated with both patient and graft survival. The retransplantation rate was 6%, and 55 patients (9.7%) have been completely weaned off immunosuppressants. Long-term patient and graft survival after pediatric LDLT for a large cohort of children at our hospital were found to be as good as those for cadaveric liver transplantation, although this series includes 13% liver transplantations with ABO-incompatible donors, which are obviously inferior in patient and graft survival. To obtain better outcomes for patients with FHF and for patients with ABO-incompatible transplants, immunosuppressive therapy needs to be improved.

Adolescent↗
PubMed2006

The role of apheresis therapy for ABO incompatible living donor liver transplantation: the Kyoto University experience.

Liver transplantation is a radical surgical therapy for end-stage liver disease. Although in Japan organ transplantation from brain-dead donors (BDD) has been allowed since October 1997, to date, only 29 liver grafts from BDD have been obtained. Thus, most of the liver transplantations carried out use living-donor liver transplantation (LDLT), and BDD liver transplantation is only used in rare cases. In order to carry out LDLT more safely, apheresis (plasmapheresis: PE) plays a major role in our country because of the prevalence of LDLT wherein later re-transplantation is difficult. Thus, because of a limited donor supply and because the needs of patients with end-stage liver disease is critical, use of grafts from ABO-incompatible (ABO-I) donors might be the only available option. From June 1990 to November 2005, 1100 patients underwent 1151 LDLT cases at Kyoto University Hospital. Additionally, 159 LDLT cases (13.8%) received ABO-I living-donor liver grafts. The role of apheresis in ABO-I LDLT is the reduction of antibody titers such as anti-A or anti-B antibody. We carry out preoperative PE as a general rule for ABO-I cases, and the recipient's antibody level against the donor's blood type is decreased to one eighth of the baseline value before LDLT. Until now, baseline immunosuppressive agents included steroids, tacrolimus and cyclophosphamide. At first, splenectomy was carried out during surgery to suppress antibody production, and intraportal (PV) infusion therapy was carried out to control local disseminated intravascular coagulation (DIC) occurring in ABO-I grafts. At that time, three drugs-methylprednisolone, prostaglandin E1 (PGE1), and gabexate mesylate (FOY) were infused continuously for 3 weeks after LDLT. At present, instead of PV infusion therapy, hepatic artery infusion therapy without splenectomy is adopted because of portal thrombosis, and two drugs- methylprednisolone and PGE1- are infused continuously for 3 weeks following LDLT. Recently, we introduced anti-CD20 monoclonal antibody (Rituximab) instead of splenectomy for B cell deletion before ABO-I LDLT. In the present article, we describe the role of apheresis around ABO-I LDLT based on our recent experiences.

ABO Blood-Group System↗
PubMed2006

[The role of statins in vascular and valvular calcification].

Vascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology, since this lesion is associated with cardiovascular disease. Statins are potent serum cholesterol-reducing drugs, which decrease the risk of cardiovascular diseases. Besides reducing serum cholesterol levels, statins are shown to decrease the rate of coronary artery calcification by unidentified mechanism. Though previous observational studies have shown that statins decrease the rate of calcific aortic valve stenosis, recent prospective study have revealed that statins are not effective against the progression of calcific aortic stenosis. We need to establish the role of statins in the prevention of aortic valve stenosis with long-term, large-scale, randomized controlled study.

Animals↗
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

The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- mice.

Both innate and adaptive immunity contribute to the progression of inflammatory-fibrotic lesions of atherosclerosis. Although platelet-derived growth factor (PDGF)-B has been investigated as a stimulant of smooth muscle cells in vascular diseases, its effects on the immune response during disease have not been evaluated in vivo. We used hematopoietic chimeras generated after lethal irradiation of ApoE-/- recipients to test the role of PDGF in atherosclerosis. Monocyte accumulation in early atherosclerotic lesions increased 1.9-fold in ApoE-/-/PDGF-B-/- chimeras. Lymphocytes from null chimeras showed a 1.6- to 2.0-fold increase in the number of activated CD4(+) T cells and a 2.5-fold elevation of interferon-gamma-secreting CD4(+) T cells on ex vivo challenge with modified low-density lipoprotein. Splenocyte transcript levels were also altered with a twofold decrease in interleukin-10 and 1.7- and 3.0-fold increases in interleukin-18 and CCR 5, respectively. These cellular and molecular changes were consistent with a shift to a proinflammatory phenotype in null chimeras. Our data also demonstrated for the first time the presence of a recently discovered family of negative regulators of innate and adaptive immunity, the suppressors of cytokine signaling (SOCS), in developing atherosclerotic lesions. Thus, our studies identify two independent negative immune regulatory pathways-PDGF-B and SOCS-that may help limit lesion expansion.

Animals↗
PubMed2005

Auxiliary partial orthotopic living donor liver transplantation: Kyoto University experience.

Auxiliary partial orthotopic liver transplantation (APOLT) was initially indicated as a potentially reversible fulminant hepatic failure and non-cirrhotic metabolic liver disease to compensate for enzyme deficiency without complete removal of the native liver. We expand our indication of APOLT for small-for-size grafts to support the function of implanted grafts during the early post-operative period, and for ABO-incompatibility to sustain a patient's life if the patient has a graft failure. We retrospectively reviewed 31 patients undergoing APOLT from living donor. The indication of APOLT was fulminant hepatic failure in 6, non-cirrhotic metabolic liver disease in 6, small-for-size grafts in 13 and ABO-incompatible cases in 6. The cumulative survival rate for APOLT at 1 and 5 years was 57.9% and 50.6%, and 78.8% and 73.8% for standard LDLT. None of the patients who underwent transplantation with APOLT for fulminant hepatic failure had long-term patient survival. The incidence of acute cellular rejection was higher in APOLT (58.1%) than standard LDLT (35.0%). Biliary complication was higher and the need for retransplantation was greater in APOLT than standard LDLT (p < 0.01). The results suggest that the indications of APOLT should be reconsidered in view of the risk for complications and retransplantation.

ABO Blood-Group System↗
PubMed2005

Therapeutic strategy and the role of apheresis therapy for ABO incompatible living donor liver transplantation.

Although in Japan, transplant organs obtained from brain-dead donors (BDD) has been allowed since October 1997, to date only 27 liver grafts from BDD have been obtained. The severe shortage of transplantable organs is a big problem, not only in liver transplantation but also other organ transplants. Liver transplantation is a fundamental treatment for end-stage liver disease. In order to perform living-donor liver transplantation (LDLT) in a safer manner, apheresis (plasmapheresis) plays a major role in Japan because of the prevalence of LDLT wherein later re-transplantation is difficult. Therefore, because of a limited donor supply and because the need of patients with end-stage liver disease is critical, use of grafts from ABO-incompatible donors may be the only available option. From June 1990 to November 2004, 1010 patients underwent 1060 LDLT cases at Kyoto University Hospital. Of these, 139 LDLT cases (13.1%) received ABO-incompatible living-donor liver grafts. The role of apheresis in ABO-incompatible LDLT is the reduction of antibody titers such as anti-A or anti-B antibody. We perform preoperative apheresis as a general rule for incompatible cases, and the recipient's antibody level against the donor's blood type is decreased to one eighth of the baseline value before LDLT. Up to the present, baseline antirejection regimens included steroids, tacrolimus and cyclophosphamide. At first, splenectomy was performed during operation to suppress antibody production, and intraportal infusion therapy was performed to control local disseminated intravascular coagulation (DIC) occurring in ABO-incompatible grafts. At that time, three agents--methylprednisolone, prostaglandin E1, and gabexate mesilate--were infused continuously for 3 weeks after LDLT. At present, instead of intraportal infusion therapy, hepatic artery infusion therapy without splenectomy is adopted because of portal thrombosis, and two agents--methylprednisolone and prostaglandin E1--are infused continuously for 3 weeks after LDLT. Recently, we introduced an anti-CD20 monoclonal antibody (Rituximab) instead of splenectomy for B cell deletion before ABO-incompatible LDLT. In this article, we describe our therapeutic strategy and the role of apheresis around ABO-incompatible LDLT.

ABO Blood-Group System↗
PubMed2005

Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure--possible involvement of nitric oxide and asymmetric NG, NG-dimethylarginine.

BACKGROUND: Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease. METHODS AND RESULTS: In the present study, flow-mediated vasodilatation (FMD) of the brachial artery and plasma concentrations of ADMA were measured before and after nasal continuous positive airway pressure (nCPAP) therapy, which abrogates apnea, in 10 male patients aged 36-69 years old, who were given a diagnosis of OSAS by polysomnography. The percent FMD (%FMD) improved significantly from 3.3+/-0.3% to 5.8+/-0.4% (p<0.01) and 6.6+/-0.3% (p<0.01), before, 1 week, and 4 weeks after nCPAP, respectively. At the same time, the plasma NOx concentrations, metabolites of NO, tended to increase, but the plasma ADMA concentration decreased inversely to %FMD and NOx. A negative correlation between %FMD and plasma ADMA concentration, and a positive correlation between %FMD and plasma NOx concentrations were observed. CONCLUSION: Nasal CPAP improves endothelial function, in part by the decreasing ADMA concentration, thereby potentiating NO production.

Adult↗
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

[Malignant lymphoma manifested by fever of unexplained origin and pure red cell aplasia in an elderly patient].

A 76-year-old woman was admitted to the University of Tokyo Hospital in June 2002 because of fever of unexplained origin. She had suffered a high grade fever (above 39 degrees C) for 2 weeks. Initial evaluation revealed elevated CRP and pancytopenia. Bone marrow aspiration (BMA) was performed, and a diagnosis of pure red cell aplasia (PRCA) was made. One month later, she complained right hypochondrial pain, and aspiration from her enlarged gall bladder was performed. Her fever and PRCA ameliorated, and she was discharged in August, 2002. In April 2003, she was readmitted to our hospital because of the recurrence of high grade fever, elevation of CRP, and pancytopenia. BMA was performed and revealed diffuse large B cell lymphoma. In the case of extranodal lymphoma which only presents pyrexia, differentiation with other diseases is very difficult especially in the elderly. It is necessary to bear in mind the possibility that a hematological malignancy, especially malignant lymphoma, can be latent in elderly patient with fever of unknown origin.

Aged↗
PubMed2005

[Current concepts of vascular calcification].

Vascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology. Two distinct forms of vascular calcification are well recognized. One is medial calcification, which occurs between the cell layers of smooth muscle cells, and is related to aging, diabetes and chronic renal failure. The other is atherosclerotic calcification, which occurs in the intima during the development of atheromatous disease. It has been shown that statins inhibit the progression of calcification in the aortic valve and the coronary artery. We have found that statins inhibit calcification of human aortic smooth muscle cells, which is induced by incubating the cells in high-phosphate medium. We also found that this is mediated by inhibiting cellular apoptosis, an essential mechanism for calcification, not by inhibiting inorganic phosphate (Pi) uptake by sodium-dependent phosphate cotransporter (NPC). Besides apoptosis and Pi uptake, such proteins as osteoprotegerin (OPG), matrix Gla protein (MGP), Klotho, fetuin-A, and apoE have been shown to negatively affect vascular calcification. Many previous reports suggest that vascular calcification appears to be regulated by promoting factors, such as Pi, apoptosis, modified LDL, advanced glycation end products, oxidative stress, vitaminD3, glucocorticoid, cbfa-1, osteopontin, and inhibitory factors, such as OPG, MGP, Klotho, fetuin-A, PTH/PTHrP, pyrophosphate, statins, and bisphosphonates. The precise mechanism of vascular calcification is of interest.

Animals↗