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Biomedical subjects

Tomohiro Nakamura

Publications and source records attributed to Tomohiro Nakamura.

16 recordsLinked to original sources
PubMed2007

Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif.

Under ambient air conditions, NO inhibits NMDAR activity by reacting with the NR2A subunit C399 along with two additional cysteine pairs if their disulfide bonds are reduced to free thiol groups [NR1(C744,C798); NR2(C87,C320)]. Here we demonstrate that relative hypoxia enhances S-nitrosylation of NMDARs by a unique mechanism involving an "NO-reactive oxygen sensor motif" whose determinants include C744 and C798 of the NR1 subunit. Redox reactions involving these two thiol groups sensitize other NMDAR sites to S-nitrosylation and consequent receptor inhibition, while their own nitrosylation has little effect on NMDAR activity. The crystal structure of the ligand-binding domain of NR1 reveals a flexible disulfide bond (C744-C798), which may account for its susceptibility to reduction and subsequent reaction with NO that is observed with biochemical techniques. These thiols may be nitrosylated preferentially during increasing hypoxia or stroke conditions, thus preventing excessive activity associated with cytotoxicity while avoiding blockade of physiologically active NMDARs.

Amino Acid Motifs↗
PubMed2006

S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol-disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.

Alzheimer Disease↗
PubMed2006

Possible vascular role of increased plasma arginine vasopressin in congestive heart failure.

BACKGROUND: The present study was undertaken to determine the relation of cardiac dysfunction with hormonal release in patients with congestive heart failure. METHODS: Seventy-two patients with congestive heart failure were examined, who were divided into four subgroups classified by the criteria of the New York Heart Association (NYHA). Also, 10 age-matched subjects were served as a control. Plasma arginine vasopressin (AVP), norepinephrine, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were determined. Cardiac index and pulmonary capillary wedge pressure (PCWP) were measured in 51 of 72 patients. RESULTS: Plasma AVP levels were significantly increased according to the severity of NYHA classes; control: 1.7 +/- 0.2; NYHA I: 4.9 +/- 0.8, NYHA II: 5.5 +/- 0.9, NYHA III: 13.4 +/- 2.6 (p < 0.05), NYHA IV: 26.9 +/- 5.6 pmol/l (p < 0.001). Similar results were obtained with plasma norepinephrine, ANP and BNP. Plasma AVP levels had negative correlation with cardiac index (r = -0.36, p < 0.01), but did not with PCWP and plasma osmolality. Plasma BNP levels positively correlated with PCWP (r = 0.44, p < 0.001), but did not with cardiac index. There was no correlation between plasma AVP and BNP. Intensive therapy profoundly reduced all the hormones according to the improvement of cardiac index in the patients with NYHA class III and IV. The percent decrease in plasma AVP was 60.0%, a value greater than that in plasma BNP. CONCLUSION: The present study indicates that increased AVP may deteriorate cardiac function through V(1a) as well as V(2) action, and that plasma AVP level is also a proper marker for the presence and severity of congestive heart failure.

Adult↗
PubMed2006

Association of hyperadiponectinemia with severity of ventricular dysfunction in congestive heart failure.

BACKGROUND: Adiponectin, which is a collagen-like plasma protein produced by adipose tissue, has anti-atherogenic and anti-inflammatory effects. Plasma adiponectin levels in patients with congestive heart failure (CHF) were determined, as well as relationships between the plasma levels of adiponectin and other hormones. METHODS AND RESULTS: The study group comprised 90 patients with CHF and 20 control subjects, who were divided into 4 subgroups according to New York Heart Association (NYHA) functional class. Plasma levels of adiponectin, tumor necrosis factor (TNF)-alpha and brain natriuretic peptide (BNP) and cardiac hemodynamics were determined. Plasma adiponectin levels were significantly increased according to the severity of NYHA class in the patients with CHF; control: 6.2+/-1.0; NYHA I: 8.5+/-1.9, NYHA II: 12.0+/-2.2, NYHA III: 13.0+/-2.7, NYHA IV: 14.9+/-2.7 microg/ml (p=0.0008). Similarly, plasma BNP levels were significantly increased in accordance with the NYHA class. Plasma adiponectin levels correlated positively with BNP (r=0.40, p=0.0002) and TNF-alpha (r=0.49, p=0.0001), and correlated negatively with cardiac index (r=-0.27, p=0.05). In 24 of 46 patients in the NYHA III and IV subgroups, according to the prompt improvement in cardiac function, levels of both plasma adiponectin and BNP were significantly reduced (p<0.0001). CONCLUSION: Plasma adiponectin levels increased according to the severity of CHF and, moreover, they correlated with the plasma levels of BNP and TNF-alpha. These results indicate that augmented release of adiponectin is involved in the pathogenesis of CHF and further study is needed to elucidate its exact role.

Adiponectin↗
PubMed2005

Up-regulated synthesis of mature-type adrenomedullin in coronary circulation immediately after reperfusion in patients with anterior acute myocardial infarction.

OBJECTIVE: Levels of adrenomedullin (AM), a potent vasodilatory peptide, have been shown to increase in the early stage of acute myocardial infarction (AMI). The purpose of this study was to determine whether coronary sinus-aortic step-up of mature forms of AM is accelerated in patients with AMI after reperfusion. METHODS: The subjects were 29 consecutive patients with a first episode of anterior AMI and 10 normal controls. All patients with AMI underwent balloon reperfusion therapy within 24 h after symptom onset. Plasma levels of two molecular forms of AM (an active, mature form [AM-m] and an intermediate, inactive glycine-extended form [AM-Gly]) in the aorta and coronary sinus (CS) were measured by specific immunoradiometric assay after reperfusion. RESULTS: Plasma levels of AM-m and AM-Gly in the aorta and CS were higher in AMI patients than in controls. CS-aortic step-up of AM-m, which is an index of myocardial production of AM-m, was significantly greater in AMI patients than in controls (1.7 +/- 1.4 vs. 0.4 +/- 0.3 pmol/L, P < 0.01). However, there was no significant difference in CS-aortic step-up of AM-Gly (P = 0.30). AMI patients with left ventricular dysfunction (n = 10) had a significantly higher CS-aortic AM-m step-up than AMI patients without left ventricular dysfunction (n = 19). AM-m in the aorta and CS negatively correlated with the left ventricular ejection fraction (r = -0.50, r = -0.48, P < 0.01). CONCLUSIONS: Myocardial synthesis of AM-m is accelerated in patients with reperfused AMI, especially in patients with critical left ventricular dysfunction. Increased myocardial synthesis of active AM may protect against cardiac dysfunction, myocardial remodeling, or both after the onset of AMI.

Adrenomedullin↗
PubMed2005

Close association of hypoadiponectinemia with arteriosclerosis obliterans and ischemic heart disease.

Adiponectin is an adipose-derived cytokine, and it is suggested that hypoadiponectinemia increases the prevalence of ischemic heart disease (IHD). The present study was undertaken to determine serum adiponectin levels in patients with arteriosclerosis obliterans (ASO) and IHD. Forty-nine patients with ASO and 49 age-, sex-, and body mass index-matched control subjects were examined. The diagnosis of ASO was derived from an ankle brachial index of less than 0.90 and stenotic or obstructive change in angiogram. Ischemic heart disease was diagnosed by ischemic or stenotic change in ECG, treadmill, or coronary angiogram. Serum adiponectin level was 8.6 +/- 0.9 microg/mL in the patients with ASO, a value significantly less than that of 12.4 +/- 1.0 microg/mL in the control subjects ( P < .01). Next, we subgrouped the subjects into 4 groups according to the presence of ASO and IHD. Serum adiponectin levels were 9.4 +/- 1.5 and 10.2 +/- 1.6 microg/mL in the subjects with ASO (n =23) and those with IHD (n = 13), respectively. It was further reduced to 7.9 +/- 1.2 microg/mL in the subjects having both ASO and IHD (n = 26), a value significantly less than that of 13.2 +/- 1.4 microg/mL in the control subjects (n = 36; P < .05). Serum high-density lipoprotein cholesterol was significantly less in the subjects with ASO than in the control subjects (42.1 +/- 1.7 vs 48.5 +/- 2.0 mg/dL; P < .05), but there were no differences in blood pressure, total cholesterol, low-density lipoprotein cholesterol, triglyceride, and uric acid levels. The present results indicate that a reduction in serum adiponectin level is associated with the prevalence and magnitude of systemic atherosclerosis including IHD and ASO.

Adiponectin↗
PubMed2005

Recurrent cardiogenic shock caused by dynamic mitral regurgitation in a patient with hypertrophic obstructive cardiomyopathy: a case report.

A 68-year-old man with hypertrophic obstructive cardiomyopathy developed recurrent cardiogenic shock due to dynamic mitral regurgitation. The pressure gradient in the left ventricular outflow tract under medication was 30 mmHg, and he complained of no symptom. He developed shock with dyspnea suddenly after bathing and defecation. Echocardiography and left ventriculography revealed massive mitral regurgitation and mild increment of pressure gradient in the left ventricular outflow tract (50 mmHg). He underwent successful mitral valve replacement following treatment with beta-blocker under intraaortic balloon pumping support. This case illustrates that exacerbation of the systolic anterior motion of the mitral anterior leaflet can cause dynamic severe mitral regurgitation with 'mild' increment of pressure gradient in the left ventricular outflow tract, resulting in cardiogenic shock with severe lung edema.

Adrenergic beta-Antagonists↗
PubMed2004

Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity.

Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure.

BACKGROUND: Impaired water excretion occurs in patients with congestive heart failure. The present study was undertaken to determine whether urinary excretion of aquaporin-2 (AQP-2) water channel is exaggerated in patients with congestive heart failure dependent upon arginine vasopressin (AVP). METHODS: Sixty-five patients with congestive heart failure and eight age- and gender-matched control subjects were examined. The patients were divided into four groups according to the criteria of New York Heart Association (NYHA). Plasma AVP levels, urinary excretion of AQP-2, and cardiac index were determined. RESULTS: Plasma AVP levels were progressively increased following the severity of NYHA class in the patients with congestive heart failure. Cardiac index was inversely decreased, and there was a negative correlation between plasma AVP levels and cardiac index (r=-0.430, P < 0.02). Urinary excretion of AQP-2 was 187.3 +/- 50.2 fmol/mg creatinine in the control subjects. It was markedly increased in the patients. Urinary excretion of AQP-2 was elevated to 1144.4 +/- 257.5 and 990.5 +/- 176.0 fmol/mg creatinine in the patients with NYHA class III and class IV, respectively, values significantly greater than the control subjects (P < 0.05). Urinary excretion of AQP-2 had a positive correlation with plasma AVP levels (r= 0.280, P < 0.02). CONCLUSION: The present study indicates that exaggerated urinary excretion of AQP-2 is dependent on baroreceptor-mediated release of AVP in patients with congestive heart failure.

Adult↗
PubMed2004

ADAM family protein Mde10 is essential for development of spore envelopes in the fission yeast Schizosaccharomyces pombe.

We report the identification of Schizosaccharomyces pombe mde10+ as a gene possessing a FLEX element, which forms a binding site for the meiosis-specific transcription factor Mei4. In fact, mde10+ is transcribed only in diploid cells that are induced to meiosis in a Mei4-dependent manner. Western blot analysis indicated that the epitope-tagged Mde10 protein accumulates transiently during meiosis and then rapidly decreases. Mde10 is a multidomain protein containing a metalloprotease catalytic domain, a disintegrin domain, a cysteine-rich domain, and membrane-spanning regions, all of which are shared by members of the mammalian ADAM family. A fusion protein of Mde10 and green fluorescent protein localized to the endoplasmic reticulum during meiosis and was located at the peripheral region of spores at the end of meiosis. An mde10Delta deletion mutant showed no apparent defects in meiosis, sporulation, or spore germination. However, the mutant spores exhibited an aberrant surface appearance, in which the ragged outer spore wall was lost to a large extent. Furthermore, mde10Delta spores were found to be less tolerant to ethanol and diethyl ether than were wild-type spores. The mutagenic replacement of the conserved glutamic acid in the putative protease active site with an alanine residue did not affect the surface morphology or the resistance of spores to environmental stress. Our observations indicate that Mde10 is important in the development of the spore envelope, although this function of Mde10 seems to be independent of its metalloprotease activity.

Alanine↗
PubMed2004

Effects of a distal protection device during primary stenting in patients with acute anterior myocardial infarction.

BACKGROUND: The angiographic no-reflow phenomenon is an adverse prognostic factor in patients with acute myocardial infarction (AMI). The aim of the present study was to evaluate the effects of an occlusive balloon type distal protection device (PercuSurge GuardWire: GW) during primary stenting in patients with anterior AMI. METHODS AND RESULTS: The GW group included 42 patients treated by primary stenting with GW protection and the control group included 30 patients treated by primary stenting after thrombectomy without distal protection. Left ventricular (LV) function was measured and compared by left ventriculography obtained soon after percutaneous coronary intervention (PCI) and 3 weeks after onset. The corrected TIMI frame count values were lower in the GW group than in the control group (27.5+/-2.3 vs 35.1 +/-2.5, p=0.030). The number of patients with myocardial blush grade 3 after PCI was higher in the GW group than in the control group (45.7 vs 20.0%, p=0.029). Peak concentration of creatine kinase myocardial fraction was lower in the GW group than in the control group (326.6+/-41.5 vs 454.9+/-46.2 mg/dl, p=0.043). GW patients showed greater improvement at 3 weeks after PCI in terms of LV ejection fraction (+4.6+/-1.2 vs -1.1+/-1.5, p=0.004), LV end-systolic volume index (+0.5+/-2.4 vs +9.0+/-2.7, p=0.023), and regional wall motion abnormalities (-2.03+/-0.14 vs -2.51+/-0.14, p=0.018). CONCLUSION: Primary stenting with GW protection can restore epicardial coronary flow and myocardial perfusion, and also preserve LV function in anterior AMI.

Blood Flow Velocity↗
PubMed2002

Increased wheel-running activity in the genetically skeletal muscle fast-twitch fiber-dominant rats.

The purpose of the present study was to investigate whether genetic differences in muscle histochemical characteristics were related to the voluntary wheel-running activity level by using genetically fast-twitch fiber-dominant rats (FFDR) and control rats (CR). The rats were divided into four groups; sedentary CR (Sed-CR), wheel-running CR (WR-CR), sedentary FFDR (Sed-FFDR), and wheel-running FFDR (WR-FFDR). Wheel access was started at age 9 wk and lasted for 7 days. The FFDR showed a lower percentage of type I fibers of the deep portion of gastrocnemius and soleus muscles and a higher percentage of both type IIX fibers of the gastrocnemius muscle and type IIA fibers of the soleus muscle compared with CR. A higher capillary density and smaller fiber cross-sectional area were also observed in FFDR. The daily running distance in WR-FFDR was higher than in WR-CR for each 7 days. The total running distance for 7 days in WR-FFDR was 3.2-fold higher than in WR-CR. On day 7 of the 7-day test, the total number of active 1-min intervals for 24 h, the average rpm when they were active, and the maximum rpm for any single 1-min period in the WR-FFDR were significantly higher than in the WR-CR (1.5-, 2.9-, and 2.0-fold, respectively). These results suggest that mechanical or physiological muscle characteristics may thus affect the wheel-running activity level.

Animals↗
PubMed2002

Chordal-sparing mitral valve replacement using artificial chordae tendineae for rheumatic mitral stenosis: experience of the "oblique" method.

Chordal-sparing mitral valve replacement (CSMVR) has been proven to be beneficial for postoperative left ventricular (LV) function. In patients with mitral stenosis, however, diseased chordae tendineae (CT) often have to be replaced using artificial CT to achieve CSMVR. Previously, we reported that resusupension of artificial CT in an oblique direction enhances systolic LV function. Among 40 consecutive patients with mitral valve replacement (MVR), 17 (4 men and 13 women; mean age 66.5 years) with rheumatic mitral stenosis underwent CSMVR with oblique resuspension. Echocardiography was done before the operation, early (mean 25 days) after the operation, and at a late stage (mean 14 months). There was no mortality or major morbidity. LV ejection fraction late after the operation (68 +/- 8%) was better than that in the early period (61 +/- 8%, p < 0.01), and comparable to the preoperative level (65 +/- 9%). The oblique method may help to improve the results of MVR.

Aged↗
PubMed2002

Novel fission yeast Cdc7-Dbf4-like kinase complex required for the initiation and progression of meiotic second division.

Cdc7, a conserved serine/threonine protein kinase, controls initiation of DNA replication. A regulatory subunit, Dbf4, stimulates the kinase activity of Cdc7 and recruits it to the replication origins. Schizosaccharomyces pombe has a homologous kinase complex, composed of Hsk1 and Dfp1/Him1. Here, we report a novel protein kinase of S. pombe, Spo4, which shares common structural features with the Cdc7 kinases. In spite of the structural similarities, Spo4 is dispensable for mitotic growth and premeiotic DNA replication. Intriguingly, spo4 null mutants are defective in initiation and progression of the second meiotic division. Spindles for meiosis II are often fragmented. Spo4 kinase activity is markedly enhanced when the enzyme is associated with its regulatory subunit, Spo6, a Dbf4-like protein. Expression of Spo4 is specifically induced during meiosis. Spo4 is preferentially present in nuclei, but this nuclear localization does not require Spo6. These results suggest that Spo4 is a Cdc7 kinase whose primary role is in meiosis, not in DNA replication. This is the first report of an organism which has two Cdc7-related kinase complexes with different biological functions.

Amino Acid Sequence↗