Biomedical subjects

H Uozumi

Publications and source records attributed to H Uozumi.

At least 19 recordsLinked to original sources

PubMed2001

Calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy.

BACKGROUND: Although activation of the Ca(2+)-dependent phosphatase calcineurin has been reported to induce cardiomyocyte hypertrophy, whether calcineurin is involved in pressure overload-induced cardiac hypertrophy remains controversial. METHODS AND RESULTS: We examined in the present study the role of calcineurin in pressure overload-induced cardiac hypertrophy using transgenic mice that overexpress the dominant negative mutant of calcineurin specifically in the heart. There were no significant differences in body weight, blood pressure, heart rate, heart weight, and the cardiac calcineurin activity between the transgenic mice and their littermate wild-type mice at basal state. The activity of calcineurin was markedly increased by pressure overload produced by constriction of the abdominal aorta in the heart of wild-type mice but less increased in the heart of the transgenic mice. Pressure overload induced increases in heart weight, wall thickness of the left ventricle, and diameter of cardiomyocytes; reprogramming of expressions of immediate early response genes and fetal-type genes; activation of extracellular signal-regulated protein kinases; and fibrosis. All these hypertrophic responses were more prominent in the wild-type mice than in the transgenic mice. CONCLUSIONS: These results suggest that calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy.

Animals↗

PubMed2001

Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin.

BACKGROUND: Extracellular signal-regulated kinases (ERKs) and calcineurin have been reported to play important roles in the development of cardiac hypertrophy. We examined here the relation between calcineurin and ERKs in cardiomyocytes. METHODS AND RESULTS: Isoproterenol activated ERKs in cultured cardiomyocytes of neonatal rats, and the activation was abolished by chelation of extracellular Ca(2+) with EGTA, blockade of L-type Ca(2+) channels with nifedipine, or depletion of intracellular Ca(2+) stores with thapsigargin. Isoproterenol-induced activation of ERKs was also significantly suppressed by calcineurin inhibitors in cultured cardiomyocytes as well as in the hearts of mice. Isoproterenol failed to activate ERKs in either the cultured cardiomyocytes or the hearts of mice that overexpress the dominant negative mutant of calcineurin. Isoproterenol elevated intracellular Ca(2+) levels at both systolic and diastolic phases and dose-dependently activated calcineurin. Inhibition of calcineurin also attenuated isoproterenol-stimulated phosphorylation of Src, Shc, and Raf-1 kinase. The immunocytochemistry revealed that calcineurin was localized in the Z band, and isoproterenol induced translocation of calcineurin and ERKs into the nucleus. CONCLUSIONS: Calcineurin, which is activated by marked elevation of intracellular Ca(2+) levels by the Ca(2+)-induced Ca(2+) release mechanism, regulates isoproterenol-induced activation of ERKs in cardiomyocytes.

Adaptor Proteins, Signal Transducing↗

PubMed2001

gp130 plays a critical role in pressure overload-induced cardiac hypertrophy.

gp130, a common receptor for the interleukin 6 family, plays pivotal roles in growth and survival of cardiac myocytes. In the present study, we examined the role of gp130 in pressure overload-induced cardiac hypertrophy using transgenic (TG) mice, which express a dominant negative mutant of gp130 in the heart under the control of alpha myosin heavy chain promoter. TG mice were apparently healthy and fertile. There were no differences in body weight and heart weight between TG mice and littermate wild type (WT) mice. Pressure overload-induced increases in the heart weight/body weight ratio, ventricular wall thickness, and cross-sectional areas of cardiac myocytes were significantly smaller in TG mice than in WT mice. Northern blot analysis revealed that pressure overload-induced up-regulation of brain natriuretic factor gene and down-regulation of sarcoplasmic reticulum Ca(2+) ATPase 2 gene were attenuated in TG mice. Pressure overload activated ERKs and STAT3 in the heart of WT mice, whereas pressure overload-induced activation of STAT3, but not of ERKs, was suppressed in TG mice. These results suggest that gp130 plays a critical role in pressure overload-induced cardiac hypertrophy possibly through the STAT3 pathway.

Animals↗

PubMed2001

Magnetic resonance imaging findings and postoperative neurologic dysfunction in elderly patients undergoing coronary artery bypass grafting.

BACKGROUND: Small cerebral infarctions are common in elderly patients, but the association between the magnetic resonance imaging finding and neurologic dysfunction after coronary artery bypass grafting has not been evaluated. METHODS: We determined, prospectively, whether varying degrees of abnormal findings on magnetic resonance images of the brain increased the incidence of preoperative cognitive decline, postoperative neuropsychological dysfunction, and stroke in 421 elderly patients (> or = 60 years) undergoing coronary artery bypass grafting. RESULTS: Control patients (almost normal or leukoaraiosis, n = 212) had rates of postoperative neuropsychological dysfunction (7%) and stroke (1.4%); the small infarctions group (some small infarctions, n = 126) had rates of 13% and 5.6%, respectively; whereas patients with multiple infarctions (multiple small infarctions or broad infarctions, n = 83) had rates of 20% and 8.4%, respectively (p = 0.004, p = 0.013). In the group with multiple infarctions, 49 patients (59%) were asymptomatic and 21 patients (25%) had cognitive decline. Stepwise logistic regression analysis demonstrated that the significant predictors of multiple small infarctions or large infarctions were history of cerebrovascular disease, renal insufficiency, cognitive decline, and cerebral arteriosclerosis. CONCLUSIONS: Multiple infarctions significantly increase the risk of neurologic dysfunction after coronary artery bypass grafting. Routine screening for preoperative cognitive decline should be performed to detect underlying ischemic cerebral disease in elderly patients.

Aged↗

PubMed2001

Growth hormone signalling and apoptosis in neonatal rat cardiomyocytes.

Growth hormone (GH) has been reported to be useful to treat heart failure. To elucidate whether GH has direct beneficial effects on the heart, we examined effects of GH on oxidative stress-induced apoptosis in cardiac myocytes. TUNEL staining and DNA ladder analysis revealed that hydrogen peroxide (H2O2)-induced apoptosis of cardiomyocytes was significantly suppressed by the pretreatment with GH. GH strongly activated extracellular signal-regulated kinases (ERKs) in cardiac myocytes and the cardioprotective effect of GH was abolished by inhibition of ERKs. Overexpression of dominant negative mutant Ras suppressed GH-stimulated ERK activation. Overexpression of Csk that inactivates Src family tyrosine kinases also inhibited ERK activation evoked by GH. A broad-spectrum inhibitor of protein tyrosine kinases (PTKs), genistein, strongly suppressed GH-induced ERK activation and the cardioprotective effect of GH against apoptotic cell death. GH induced tyrosine phosphorylation of EGF receptor and JAK2 in cardiac myocytes, and an EGF receptor inhibitor tyrphostin AG1478 and a JAK2 inhibitor tyrphostin B42 completely inhibited GH-induced ERK activation. Tyrphostin B42 also suppressed the phosphorylation of EGF receptor stimulated by GH. These findings suggest that GH has a direct protective effect on cardiac myocytes against apoptosis and that the effect of GH is attributed at least in part to the activation of ERKs through Ras and PTKs including JAK2, Src, and EGF receptor tyrosine kinase.

Animals↗

PubMed2000

Superselective embolisation for intractable idiopathic epistaxis.

37 patients with intractable idiopathic epistaxis were treated with superselective embolisation between 1995 and 1999. A total of 40 embolisations was performed, including three procedures for recurrence. The embolic material was gelatin sponge in 27 procedures, microcoils in 9 and both gelatin sponge and microcoils in 4. Immediate cessation of nasal bleeding was obtained in all patients after embolisation. Recurrent epistaxis occurred in 2 (5.4%) of the 37 patients within 7 days after initial embolisation, giving a short-term success rate of 94.6%. The long-term follow-up ranged from 1-51 months (mean 21.6 months). Late re-bleeding occurred in two patients, giving a long-term success rate of 94.6%. Two patients underwent re-embolisation; it was necessary to embolise the ipsilateral facial artery and/or the contralateral internal maxillary as well as the ipsilateral maxillary artery. Although the overall complication rate was 45.0%, no major complications occurred. Superselective embolisation with gelatin sponge is an effective and safe treatment technique for intractable idiopathic epistaxis.

Adult↗

PubMed1999

Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.

BACKGROUND: Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment. CONCLUSIONS: The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.

Animals↗

PubMed1999

MAPK superfamily plays an important role in daunomycin-induced apoptosis of cardiac myocytes.

BACKGROUND: Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, including cardiac toxicity. In the present study, we investigated the molecular mechanisms of DM-induced cardiomyocyte impairment. METHODS AND RESULTS: When cultured cardiac myocytes of neonatal rats were exposed to 1 micromol/L DM for 24 hours, many cells became positive for TUNEL staining, with morphological changes characteristic of apoptosis. Fragmentation of DNA into oligonucleosome-size fragments was recognized by agarose gel electrophoresis in DM-treated myocytes. DM activated 3 members of the mitogen-activated protein kinase (MAPK) family dose-dependently, such as extracellular signal-regulated protein kinases (ERKs), c-Jun NH(2)-terminal kinases, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca(2+) chelators inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activation of ERKs was also inhibited by overexpression of dominant negative mutants of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ERK signaling pathway was selectively blocked by a specific MAPK/ERK kinase inhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MAPK, SB203580, significantly reduced the amount of apoptosis. CONCLUSIONS: These results suggest that DM activates MAPKs through reactive oxygen species and Ca(2+) and that the MAPK family plays important roles in DM-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from apoptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte apoptosis.

Animals↗

PubMed1999

Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy.

Activation of beta-adrenoreceptors induces cardiomyocyte hypertrophy. In the present study, we examined isoproterenol-evoked intracellular signal transduction pathways leading to activation of extracellular signal-regulated kinases (ERKs) and cardiomyocyte hypertrophy. Inhibitors for cAMP and protein kinase A (PKA) abolished isoproterenol-evoked ERK activation, suggesting that Gs protein is involved in the activation. Inhibition of Gi protein by pertussis toxin, however, also suppressed isoproterenol-induced ERK activation. Overexpression of the Gbetagamma subunit binding domain of the beta-adrenoreceptor kinase 1 and of COOH-terminal Src kinase, which inhibit functions of Gbetagamma and the Src family tyrosine kinases, respectively, also inhibited isoproterenol-induced ERK activation. Overexpression of dominant-negative mutants of Ras and Raf-1 kinase and of the beta-adrenoreceptor mutant that lacks phosphorylation sites by PKA abolished isoproterenol-stimulated ERK activation. The isoproterenol-induced increase in protein synthesis was also suppressed by inhibitors for PKA, Gi, tyrosine kinases, or Ras. These results suggest that isoproterenol induces ERK activation and cardiomyocyte hypertrophy through two different G proteins, Gs and Gi. cAMP-dependent PKA activation through Gs may phosphorylate the beta-adrenoreceptor, leading to coupling of the receptor from Gs to Gi. Activation of Gi activates ERKs through Gbetagamma, Src family tyrosine kinases, Ras, and Raf-1 kinase.

Animals↗

PubMed1998

Role of ion channels and exchangers in mechanical stretch-induced cardiomyocyte hypertrophy.

We have previously reported that stretching of cardiomyocytes activates the phosphorylation cascade of protein kinases, including Raf-1 kinase and mitogen-activated protein (MAP) kinases, followed by an increase in protein synthesis partly through enhanced secretion of angiotensin II and endothelin-1. Membrane proteins, such as ion channels and exchangers, have been postulated to first receive extracellular stimuli and evoke intracellular signals. The present study was performed to determine whether mechanosensitive ion channels and exchangers are involved in stretch-induced hypertrophic responses. Neonatal rat cardiomyocytes cultured on expandable silicone dishes were stretched after pretreatment with a specific inhibitor of stretch-sensitive cation channels (gadolinium and streptomycin), of ATP-sensitive K+ channels (glibenclamide), of hyperpolarization-activated inward channels (CsCl), or of the Na+-H+ exchanger (HOE 694). Pretreatment with gadolinium, streptomycin, glibenclamide, and CsCl did not show any inhibitory effects on MAP kinase activation by mechanical stretch. HOE 694, however, markedly attenuated stretch-induced activation of Raf-1 kinase and MAP kinases by approximately 50% and 60%, respectively, and attenuated stretch-induced increase in phenylalanine incorporation into proteins. In contrast, HOE 694 did not inhibit angiotensin II-and endothelin-1-induced Raf-1 kinase and MAP kinase activation. These results suggest that among many mechanosensitive ion channels and exchangers, the Na+-H+ exchanger plays a critical role in mechanical stress-induced cardiomyocyte hypertrophy.

Angiotensin II↗

PubMed1997

Cerebral ischemic disorders and cerebral oxygen balance during cardiopulmonary bypass surgery: preoperative evaluation using magnetic resonance imaging and angiography.

We compared the preoperative prevalence of small cerebral infarctions and carotid stenosis to jugular venous oxygen saturation (Sjvo2) during coronary artery bypass grafting (CABG). Sjvo2 served as an indicator of whether cerebral oxygen supply meets demand in patients on cardiopulmonary bypass (CPB). The study population consisted of 121 patients who were either older than 65 yr or had a history of cerebrovascular disease. The patients underwent preoperative cerebral magnetic resonance imaging (MRI) and cervical magnetic resonance angiography (MRA) to detect small cerebral infarctions and carotid artery stenosis. Patients with atherosclerosis of the ascending aorta were identified by intraoperative epiaortic ultrasonography. Liberation of emboli from the aorta in these patients was prevented by modification of the standard operation. From preoperative MRI and MRA, 65 patients (54%) had small cerebral infarctions in the white matter or basal ganglia and nine patients (7%) demonstrated moderate or severe stenosis in the carotid arteries. Thirteen patients (11%) had moderate or severe atheromatous disease of the ascending aorta. The severity of aortic atherosclerosis was significantly correlated with the grade of carotid stenosis (P < 0.05). In patients with small infarctions, Sjvo2 was significantly lower than in patients without infarctions (controls) at initiation of CPB, 30 min after aortic cross-clamping, and during the rewarming period of CPB (P < 0.05). Thus, small cerebral infarctions were not uncommon in elderly patients undergoing CABG. Patients with small cerebral infarctions may be at risk for an imbalance in cerebral oxygen supply and demand during the rewarming period because they are unable to deliver the necessary compensatory blood flow.

Aged↗

PubMed1996

Lattice corneal dystrophy type II associated with familial amyloid polyneuropathy type IV.

BACKGROUND: Finnish-type familial amyloidosis (FAP-IV) is an autosomal, dominantly inherited disorder characterized by progressive polyneuropathy and lattice corneal dystrophy type II. The vast majority of families with this disorder originated from Finland. Only two families, in neighboring districts, have been reported in Japan previously. METHODS: The authors report two additional Japanese patients with FAF-IV. The proband, a 70-year-old man, had decreased perspiration and abnormal facial muscle movement. Results of neurologic examination showed bilateral facial and hypoglossal nerve palsies, and an autonomic disturbance, including orthostatic hypotension and dysfunction of perspiration. Histochemical, immunohistological, and DNA studies confirmed the diagnosis of FAP-IV. RESULTS: Results of ophthalmologic examination showed asymptomatic lattice corneal dystrophy of both eyes, but the appearance of the cornea was different from that described in the patients from Finland. Lattice lines in the authors' patient were very fine, short, and glassy and could be observed with indirect retroillumination, but might be missed with direct illumination by the slit-lamp microscope. The proband's younger half-sister, a 68-year-old woman, showed clinical findings and laboratory data similar to those of the proband. CONCLUSION: The authors report two Japanese patients with lattice corneal dystrophy type II related to FAP-IV. This is the third Japanese family with this disorder, and there is no familial relationship to the two previously reported families in Japan.

Aged↗

PubMed1996

Short communication: the value of embolization therapy in painful osseous metastases from hepatocellular carcinomas; comparative study with radiation therapy.

We evaluated the therapeutic effect of transcatheter arterial embolization therapy (TAE) for painful osseous metastases from hepatocellular carcinoma (HCC) in comparison with radiation therapy (RT). TAE using gelatin sponge particles was performed for seven lesions in seven patients. Selective catheterization and embolization were successfully performed in all lesions. Within 10 days after TAE, complete pain relief (CR), partial relief (PR) and no relief (NR) were attained in 57%, 29% and 14%, respectively. RT was used to treat 34 lesions in 22 patients. The dose fractionation schedules were in the range 28.0-50.4 Gy, with 1.8-4.0 Gy per fraction. CR, PR and NR were attained in 47%, 47% and 6%, respectively. There were no serious complications related to these treatments. Both TAE and RT are effective and the treatment of choice should be selected on an individual basis.

Bone Neoplasms↗

PubMed1990

[Pathogenesis and prevention of gastrointestinal complications following transcatheter arterial embolization].

Prospective evaluation of gastrointestinal complications after transcatheter arterial embolization (TAE) was performed on 149 TAEs of 133 patients with endoscopy in order to evaluate whether the use of antiulcer medication can prevent such complications. In 21 of 141 TAEs (14%) there developed gastrointestinal complications. The incidence of complications with administration of H2-blocker was 30.4%, whereas the incidence with administration of PGE1 and without medication were 2.8% (p less than 0.01) and 9.0%, respectively. It has been suggested that such complications are mainly due to backflow of the embolic materials to the gastric artery. These findings indicates that decrease of gastric mucosal blood flow due to backflow of the embolic materials to the gastric artery cause the gastrointestinal complications.

Anti-Ulcer Agents↗

PubMed1990

Radiation therapy of invasive thymoma.

Between 1978 and 1987, 30 cases of invasive thymomas were treated with radiotherapy after surgery. Surgical therapy consisted of total resection in 15 patients, subtotal resection in 1 patient, and biopsy in 14 patients. Myasthenia gravis (MG) was associated in nine patients (MG(+) group), but in 21 patients there was no evidence of myasthenia gravis (MG(-) group). Irradiation in the dose range of 30 to 58.7 Gy was delivered. The total average 5-year survival rate was 71.8%; it was 39.2% in MG(+) group and 78.3% in MG(-) group, though there was no significant statistical difference. Myasthenia gravis was well controlled by the tumorectomy and associated radiotherapy in 7 of the 9 patients. However, in 3 of 7 patients (42.9%) myasthenia gravis recurred at 2 years, 2 years and 7 months, and 5 years and 8 months after initial therapy. Total body irradiation of 2 Gy with 0.1 Gy fractions was administered for uncontrollable myasthenia gravis in one patient with marked improvement. Radiation therapy is an important therapeutic modality for unresectable malignant thymoma as well as for postoperative combined therapy. Total body irradiation may be an effective method to treat patients with otherwise resistant myasthenia gravis.

Adolescent↗

PubMed1988

[A case of recurrent epipharyngeal cancer showing complete disappearance following suppository administration of tegafur (Sunfural rectal capsules)].

A 55-year-old woman was diagnosed as having epipharyngeal cancer, characterized by T2N1M0 and poorly differentiated squamous cell carcinoma. She was treated by radiotherapy (primary site: 65 Gy, neck: 75 Gy) and the tumor completely disappeared. However, 4 months later, the tumor recurred in the epipharynx. Tegafur in the form of a suppository (Sunfural Rectal Capsules, 750 mg) was given once a day. During the course of epipharyngoscopic follow-up the tumor almost totally disappeared at a dose of 10,250 mg (15 days). Biopsy failed to reveal any cancer cells and computed tomography showed no tumor masses in the epipharynx. At present, 6 months have already passed since the start of Tegafur administration, there is no recurrence of the cancer, and the chemotherapy is being continued at our outpatient clinic. By the standard for the efficacy of cancer chemotherapy proposed by Koyama and Saito, this case corresponds to a state of complete response.

Carcinoma, Squamous Cell↗

PubMed1987

Radiotherapy of spontaneous carotid-cavernous sinus fistulas.

Between 1984 and 1986, 7 patients with spontaneous carotid-cavernous fistulas (CCF) were treated by radiotherapy delivering 3,000 cGy (200 cGy, 5 times per week) to the sellar region. Improvements of clinical signs and symptoms were seen in all patients within 6 months of treatment. During a follow-up period of 7 to 35 months, 6 patients remained in good clinical condition and only one patient developed a recurrence. As an adverse effect, one patient developed early menopause, but no other side-effects or complications were seen. Radiotherapy should be considered in patients with spontaneous CCF, when CCF are seen in middle-high aged patients and progressive without relief of symptoms.

Adult↗

PubMed1986

Primary carcinoid tumor of the liver: a case report.

A very rare case of primary carcinoid tumor of the liver that underwent hepatic artery embolization is reported. Computed tomography showed a low-density tumor with little contrast medium enhancement, whereas angiography revealed a slightly hypervascular mass in the liver. The computed tomography findings after hepatic artery embolization showed a marked decrease in attenuation and gas formation.

Carcinoid Tumor↗