Hiroshi Iwao

Osaka City University, Ōsaka, Ōsaka, Japan

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Publications (263)938.29 Total impact

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    ABSTRACT: Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase, and induces radiographic regression and symptomatic improvement in patients with non-small cell lung cancer (NSCLC). Phase II trials suggested female sex and adenocarcinoma were associated with response, never smoking history and adenocarcinoma were associated with survival. We attempted to identify additional clinical features associated with response and survival. We reviewed medical records and imaging studies of all 68 NSCLC patients treated by gefitinib monotherapy in our institution. We identified patients experiencing disease control and compared their clinical features with those of other patients. We considered partial response, stable disease or incomplete response and stable disease to be evidence of disease control. Univariate and multivariate analysis were performed to determine predictive and prognostic factors associated with disease control and survival. Of 68 patients, 20 (29.4%) experienced disease control. Variables identified as significant for disease control with gefitinib included never smoking history (p=0.0128) and history of curative surgical resection (p=0.0007) on multivariate analysis. Variables identified as significant for overall survival included never smoking history (p=0.0128), history of curative surgical resection (p=0.0007), and performance status (PS) of 0 and 1 (p=0.0001) on multivariate analysis. Our findings suggest that never smoking history and history of curative surgical resection are key factors for disease control and prognostic factors in patients with NSCLC treated with gefitinib.
    Osaka city medical journal 07/2006; 52(1):1-8.
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    ABSTRACT: Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia. The purpose of this study was to examine the effects of EPO on cardiac remodeling after myocardial infarction (MI). MI was induced by ligation of the coronary artery in Wistar rats. The rats with MI were randomly divided into untreated MI and two EPO-treated MI groups. EPO was administered subcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 times a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the increase in activated caspase 3, matrix metalloproteinase-2, and transcriptional activation of activator protein-1 in non-infarcted myocardium. Four weeks after MI, left ventricular weight, left ventricular end-diastolic pressure, and left ventricular dimension were increased, and ejection fraction and E wave deceleration time were decreased. EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction. In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium. Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis.
    Journal of Pharmacological Sciences 06/2006; 101(1):31-9. DOI:10.1254/jphs.FP0050966 · 2.11 Impact Factor
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    ABSTRACT: To examine the effects of microbubble destruction with ultrasound (MB) combined with bone marrow derived mononuclear cell transplantation (BMT) into ischaemic tissues in rat hind limb ischaemia. Unilateral hind limb ischaemia was surgically induced in Lewis rats. At postoperative day 7, rats were randomly divided into three groups: a vehicle treated group, an ultrasound treated group, and an MB treated group. MB treatment increased vascular endothelial growth factor mRNA as assessed by real time polymerase chain reaction (3.0-fold, p < 0.05). At four weeks, the MB group had increases in laser Doppler blood flow index (LDBFI; 1.2-fold, p < 0.05), angiographically detectable collateral vessels (angiographic score: 1.4-fold, p < 0.01), and capillary to muscle fibre ratio (1.4-fold, p < 0.01) in ischaemic limbs compared with the vehicle treated group. No differences were seen between the vehicle and ultrasound treated groups. Secondly, rats were allocated to vehicle treatment, BMT (5 x 10(6) cells/rat), or a combination of MB and BMT (MB+BMT) at seven days after hind limb ischaemia. BMT treatment significantly increased LDBFI, angiographic score, and capillary to muscle fibre ratio compared with vehicle treatment. Interestingly, MB+BMT treatment produced significantly greater LDBFI (1.2-fold, p < 0.01), angiographic score (1.5-fold, p < 0.01), and capillary to muscle fibre ratio (1.5-fold, p < 0.05) than BMT treatment alone. MB may be a useful technique to enhance BMT induced neovascularisation.
    Heart (British Cardiac Society) 04/2006; 92(4):515-20. DOI:10.1136/hrt.2005.064162 · 6.02 Impact Factor
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    ABSTRACT: Background: Measurement of the coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography (TTDE) has been reported to be useful for the noninvasive assessment of significant coronary artery stenosis or myocardial ischemia. The purpose of this study was to evaluate the value of this method in three major coronary arteries for detecting myocardial ischemia in the clinical setting. Methods: We studied 89 consecutive patients who were referred to our outpatient clinic because of chest pain. We measured CFVR using TTDE in three major coronary arteries. We defined CFVR < 2.0 in at least one vessel as being positive for myocardial ischemia. The accuracy of CFVR measurements for detecting myocardial ischemia was determined in comparison with exercise thallium-201 (Tl-201) single photon emission computed tomography (SPECT) as a reference standard. Results: CFVR in at least one vessel was successfully measured in 87 of 89 patients (98%). The sensitivity and specificity of CFVR < 2.0 in at least one coronary vessel, in any of the coronary territories, was 86% and 89%, respectively. In terms of assessing myocardial ischemia in each coronary artery territory, the agreement between CFVR < 2.0 and Tl-201 SPECT for the left anterior descending coronary artery, the posterior descending coronary artery, and the left circumflex coronary artery territories was 95%, 81%, and 73%, respectively. Conclusion: Noninvasive CFVR measurement by TTDE may be useful for detecting myocardial ischemia, as well as for identifying ischemic territories in the clinical setting.
    Echocardiography 03/2006; 23(4):279 - 286. DOI:10.1111/j.1540-8175.2006.00206.x · 1.25 Impact Factor
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    ABSTRACT: Cardiac activator protein-1 (AP-1), composed of c-Jun, is significantly activated by hypertension or angiotensin II (AngII). This study was undertaken to elucidate whether c-Jun could be the potential target for treatment of cardiac hypertrophy. We constructed recombinant adenovirus carrying dominant-negative mutant of c-Jun (Ad.DN-c-Jun). Using catheter-based technique of adenoviral gene transfer, we achieved global myocardial transduction of DN-c-Jun in rats, to specifically inhibit cardiac AP-1. (1) AngII (200 ng/kg/min) infusion in rats caused cardiac hypertrophy, increased cardiac p70S6 kinase activity by 1.3-fold (P<0.05) and enhanced the gene expression of cardiac hypertrophic markers. Ad.DN-c-Jun, which was transferred to the heart 2 days before AngII infusion, prevented cardiac hypertrophy (P<0.01), decreased p70S6 kinase phosphorylation (P<0.05), and suppressed cardiac gene expression of brain natriuretic peptide, collagen I, III, and IV, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) (P<0.01). (2) In genetically hypertensive rats with cardiac hypertrophy, cardiac gene transfer of Ad.DN-c-Jun, without affecting hypertension, regressed cardiac hypertrophy (P<0.05), and suppressed p70S6 kinase phosphorylation by 20% (P<0.05) and suppressed the enhanced expression of collagen I, III, and IV, MCP-1 and PAI-1. These results provided the first evidence that in vivo blockade of cardiac c-Jun inhibits pathologic cardiac hypertrophy.
    Gene Therapy 03/2006; 13(4):348-55. DOI:10.1038/sj.gt.3302670 · 4.20 Impact Factor
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    ABSTRACT: To examine the effects of eplerenone, a selective aldosterone blocker, on cardiac function after myocardial infarction (MI) and myocardial remodelling related transcriptional factors and mRNA expression in non-infarcted myocardium. MI was induced by ligation of the coronary artery in Wistar rats. Rats were randomly assigned to a vehicle treated group or an eplerenone treated group (100 mg/kg/day). At four weeks after MI, left ventricular (LV) end diastolic pressure, LV weight, and LV end diastolic dimension were increased in MI rats. Eplerenone significantly reduced the increase in LV end diastolic pressure, LV weight, and LV end diastolic dimension. In the MI rats the decreased ejection fraction indicated systolic dysfunction and the increased E wave to A wave ratio and E deceleration rate indicated diastolic dysfunction. Eplerenone significantly attenuated this systolic and diastolic dysfunction. Myocardial interstitial fibrosis, transcriptional activities of activator protein 1 and nuclear factor kappaB, and mRNA expression of monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, atrial natriuretic peptide, brain natriuretic peptide, and collagen types I and III were significantly increased at four weeks after MI. Eplerenone significantly attenuated interstitial fibrosis and suppressed transcriptional activity and mRNA expression of these genes. When administered after MI, eplerenone prevents cardiac remodelling accompanied by systolic and diastolic dysfunction and inhibits abnormal myocardial transcriptional activities and gene expression.
    Heart (British Cardiac Society) 01/2006; 91(12):1595-600. DOI:10.1136/hrt.2004.046540 · 6.02 Impact Factor
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    ABSTRACT: Rapamycin-coated stents in coronary artery lesions have recently been shown to be effective in inhibiting neointimal formation. However, little is known about the effects of rapamycin on mitogen-activated protein kinase (MAPK), which is an important signal for neointimal formation. Therefore, we examined the effects of rapamycin on MAPK and transcriptional factors in cultured human coronary artery smooth muscle cells (CASMC) and in balloon-injured rat carotid arteries. Activation of ERK, JNK, p38MAPK, AP-1, and NF-kB in coronary artery smooth muscle cells was increased by 2% fetal bovine serum. Ten nmol/L of rapamycin prevented the activation of JNK, p38MAPK, AP-1, and NF-kB (65%, 65%, 67%, and 26% respectively, P<0.01). In an in vivo study, remarkable neointimal formation was observed 14 days after injury. Coating Pluronic gel with 20 and 50 mug rapamycin around the injured artery significantly decreased the intimal area/medial area ratio, compared with vehicle (0.75 vs. 1.2, P<0.01). Rapamycin prevented the increase in activation of JNK, p38MAPK, AP-1, and NF-kB in injured artery (42%, 70%, 75%, and 60% respectively, P<0.05). Neointimal formation after balloon injury is inhibited by rapamycin, which is partially mediated by inhibition of JNK and p38MAPK, followed by AP-1 and NF-kB.
    Journal of Cardiovascular Pharmacology 11/2005; 46(4):519-25. DOI:10.1097/01.fjc.0000179001.00779.a5 · 2.11 Impact Factor
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    ABSTRACT: We first examined the role of apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, in ischemia-induced angiogenesis. Unilateral hindlimb ischemia was induced surgically in C57BL/6J wild-type (WT) mice or mice deficient in ASK1 (ASK1(-/-)). ASK1 activity in WT mouse hindlimb was increased dramatically after ischemia. By laser Doppler analysis, well-developed collateral vessels and angiogenesis were observed in WT mice in response to hindlimb ischemia, whereas these responses were reduced in ASK1(-/-) mice. Immunostaining revealed that infiltration of macrophages and T lymphocytes was suppressed in the ischemic tissues of ASK1(-/-) mice compared with WT mice. The expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) proteins in ischemic tissues was weaker in ASK1(-/-) mice compared with WT mice. In vitro study on endothelial cells indicated that dominant-negative ASK1 significantly attenuated hydrogen peroxide-induced VEGF and MCP-1 production. Furthermore, in vivo blockade of MCP-1 by its neutralizing antibody suppressed the recovery of the blood flow and capillary formation after ischemia. ASK1 pathway promotes early angiogenesis by inducing inflammatory cell infiltration and VEGF and MCP-1 expression. ASK1 may provide the basis for the development of new therapeutic strategy for angiogenesis.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2005; 25(9):1877-83. DOI:10.1161/01.ATV.0000174801.76234.bd · 5.53 Impact Factor
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    ABSTRACT: Because granulocyte-colony stimulating factor (G-CSF) mobilizes bone marrow cells including endothelial progenitor cells, we examined whether G-CSF augments angiogenesis and collateral vessel formation induced by bone marrow-mononuclear cells transplantation (BMT). Unilateral hindlimb ischemia was surgically induced in Lewis rats. One week after surgery, administration of 100 mg/kg per day G-CSF significantly increased the laser Doppler blood perfusion index (LDBPI), number of angiographically detectable collateral vessels (angiographic score), and capillary density determined by alkaline phosphatase staining. In the BMT group (1 x 10(7) cells/rat) and the group with combined G-CSF treatment and BMT, LDBPI was significantly increased compared with that in the vehicle-treated group. In the BMT group, neovascularization was significantly increased as evidenced by the angiographic score and capillary density compared with the vehicle-treated group. Furthermore, the combination of G-CSF treatment and BMT augmented neovascularization compared with BMT alone, as evidenced by the angiographic score and capillary density. Moreover, G-CSF significantly increased vascular endothelial growth factor mRNA and fibroblast growth factor-2 mRNA in hindlimb muscle. In conclusion, G-CSF was found to augment neovascularization in rat hindlimb ischemia. Combined use of G-CSF treatment and BMT may be a useful strategy for therapeutic neovascularization in ischemic tissues.
    Journal of Pharmacological Sciences 10/2005; 99(1):45-51. DOI:10.1254/jphs.FP0040966 · 2.11 Impact Factor
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    ABSTRACT: In this study, we examined whether an angiotensin II type 1 (AT1)-receptor blocker improves diastolic heart failure (DHF) in Dahl salt-sensitive (DS) rats. DHF was prepared by feeding DS rats on 8% NaCl diet from 7 weeks of age. DHF was estimated with echocardiography by measuring E velocity / A velocity (E/A) of left ventricular inflow. DS rats with established DHF were orally given candesartan (1 mg/kg per day) or vehicle. After 13 days of treatment, candesartan significantly improved DHF, as shown by the reduction of E/A from 4.49 +/- 1.04 to 1.98 +/- 0.54 (P<0.05) and prolonged survival rate more than the vehicle. Cardiac fibrosis, apoptosis, and gene expression were estimated by Sirius Red-staining, TUNEL-staining, and Northern blot analysis, respectively. The improvement of DHF by candesartan was accompanied by the decrease in cardiac hypertrophy, fibrosis, and apoptosis, and the reduction of gene expression of brain natriuretic peptide, collagen I, and monocyte chemoattractant protein-1. Moreover, candesartan decreased cardiac inflammatory cells and reactive oxygen species, estimated by counting ED-1-positive cells and the measurement of 4-hydroxy-2-nonenal staining, respectively. These results indicate that candesartan can improve diastolic dysfunction and may slow the progression of cardiac remodelling in DS rats with established DHF.
    Journal of Pharmacological Sciences 09/2005; 98(4):372-9. DOI:10.1254/jphs.FP0050160 · 2.11 Impact Factor
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    ABSTRACT: It is well known that angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers (ARBs) prevent left ventricular (LV) remodelling after myocardial infarction (MI). However, it is still not clear whether inhibition of the AT1 receptor is enough to prevent LV remodelling after MI. To elucidate the effects of ACE inhibitors that are not mediated by the AT1 receptor on LV remodelling, MI was experimentally induced in wild-type (WT-MI) mice and AT1 receptor knockout (KO-MI) mice. Mice were divided into six groups: WT-control, KO-control, WT-MI, KO-MI, WT-MI treated with an ACE inhibitor, and KO-MI treated with an ACE inhibitor. Four weeks after MI, cardiac function was assessed by Doppler echocardiography and non-infarcted myocardial mRNA expression by northern blot analysis. Cardiac function decreased significantly in the MI groups compared with the sham operated groups. Additionally, in the MI groups end diastolic dimension, E wave velocity, the ratio of peak velocity of E wave to A wave, deceleration rate of E wave, and mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and collagens I and III increased significantly compared with the sham groups. LV remodelling after MI was prevented in KO-MI mice compared with WT-MI mice. ACE inhibitor administration significantly attenuated progressive LV remodelling in both WT and KO-MI groups. ACE inhibitors can prevent the LV remodelling process that accompanies cardiac dysfunction after MI, even in AT1 KO mice. These findings suggest that ACE inhibitors prevent LV remodelling after MI by mechanisms other than inhibition of angiotensin AT1 receptor mediated effects.
    Heart (British Cardiac Society) 09/2005; 91(8):1080-5. DOI:10.1136/hrt.2004.035618 · 6.02 Impact Factor
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    ABSTRACT: Osteopontin has been reported to have an important role in cardiac fibrosis. However, little is known about the effects of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blockers (ARB) on osteopontin expression in infarcted myocardium. The purpose of this study was to elucidate the effects of an ACEI (perindpril) and an ARB (candesartan cilexitil) on cardiac function as assessed by Doppler echocardiography and cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted rats. ACEI or ARB was administered after myocardial infarction (MI). At 4 weeks after MI, cardiac function, and mRNAs in non-infarcted myocardium were analyzed. ACEI and ARB equally prevented left ventricular dilatation, reduction of ejection fraction, and the increase in E/A wave velocity ratio and the rate of E wave deceleration by MI. ACEI and ARB significantly suppressed increased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, osteopontin, and collagen I and III in the non-infarcted ventricle at 4 weeks. Immunohistochemically stained osteopontin was increased in interstitial fibrosis of non-infarcted myocardium. Both ACEI and ARB significantly prevented cardiac fibrosis and osteopontin expression. In conclusion, angiotensin blockade inhibits osteopontin expression in non-infarcted myocardium and prevents cardiac remodeling after MI.
    Journal of Pharmacological Sciences 08/2005; 98(3):283-9. DOI:10.1254/jphs.FP0050056 · 2.11 Impact Factor
  • Journal of Cerebral Blood Flow & Metabolism 07/2005; 25:S528-S528. DOI:10.1038/sj.jcbfm.9591524.0528 · 5.34 Impact Factor
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    ABSTRACT: A timed non-invasive determination of cardiac function is potentially important for safety pharmacology and toxicity studies. The objectives of this study were to evaluate the accuracy of real-time three-dimensional (RT3D) echocardiography measurements of the left ventricular (LV) volume and LV function and to investigate the effects of some drugs on LV function in cynomolgus monkeys. RT3D echocardiography was performed (SONOS 7500, Philips Med Sys) under isoflurane inhalation. RT3D echocardiography measurements and reconstructions were obtained using Tom-Tec (4DLV analysis). We determined end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), stroke volume (SV), cardiac output (CO) and heart rate as assessments of LV function. EDV, calculated from two-dimensional (2D) echocardiography and RT3D echocardiography, and the actual LV volume were evaluated and compared. Furthermore, each parameter was determined before and after intravenous infusion (5 or 10 min) of propranolol, verapamil and dobutamine. A strong correlation was found between the actual LV volume and that calculated from RT3D echocardiography (r=0.96, p<0.001). Propranolol (0.1 mg/kg/10 min, n=5) caused an increase in ESV, but not EDV, resulting in a decrease in EF and SV, while verapamil produced increases in both EDV and ESV. Dobutamine (0.01 mg/kg/5 min, n=5) produced decreases in both EDV and ESV and thereby the increased CO resulted from the increased SV. These results demonstrate that RT3D echocardiography provides a feasible and accurate estimation of LV volume and EF for safety pharmacology and toxicity studies.
    Journal of Pharmacological and Toxicological Methods 07/2005; 52(1):182-7. DOI:10.1016/j.vascn.2005.04.003 · 2.15 Impact Factor
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    ABSTRACT: Aldosterone is known to play a role in the pathophysiology of some cardiovascular diseases. However, previous studies on aldosterone infusion have been mostly performed in animals receiving sodium loading and uninephrectomy, and thus the cardiac action of aldosterone alone remains to be fully clarified. The present study was undertaken to investigate the direct cardiac action of aldosterone infusion alone in rats not subjected to salt loading and uninephrectomy. Aldosterone (0.75 microg/h) was subcutaneously infused into rats via an osmotic minipump for 14 days. Aldosterone infusion, under a normal salt diet, induced only a slight increase in the blood pressure of normal rats throughout the infusion. However, aldosterone significantly induced cardiac hypertrophy, as shown by echocardiography and measurement of cardiomyocyte cross-sectional area. Furthermore, aldosterone caused not only cardiac interstitial macrophage infiltration but also cardiac focal inflammatory lesions, which were associated with an increase in cardiac monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNA. The slight elevation of blood pressure by aldosterone infusion was completely prevented by tempol, the superoxide dismutase mimetic. However, tempol failed to suppress cardiac hypertrophy, the formation of inflammatory lesions, and upregulation of cardiac MCP-1 and osteopontin by aldosterone, while N-acetylcysteine could inhibit all of them. Our data provide evidence that aldosterone alone can induce cardiac hypertrophy and severe inflammatory response in the heart, independently of blood pressure, even in the absence of salt loading or nephrectomy. Aldosterone seems to induce cardiac inflammation and gene expression via oxidative stress that is inhibited by N-acetylcysteine but not by tempol.
    Hypertension Research 06/2005; 28(5):447-55. DOI:10.1291/hypres.28.447 · 2.94 Impact Factor
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    ABSTRACT: The detailed role of angiotensin II in salt-exacerbated stroke is unclear. We examined the role of angiotensin II in salt-accelerated stroke of stroke-prone spontaneously hypertensive rats (SHRSP). Salt-loaded SHRSP were orally given the angiotensin II type 1 (AT1) receptor blocker candesartan (0.3 to 3 mg/kg per day) and calcium channel blocker amlodipine (1 mg/kg per day), and the effects on stroke (n=61) and brain superoxide were compared between them. We also examined the effect of angiotensin II infusion (200 ng/kg per min) on brain superoxide production and blood-brain barrier. Despite the comparable hypotensive effect between candesartan and amlodipine, candesartan prolonged survival of salt-loaded SHRSP much more than amlodipine (P<0.01), being associated with more improvement of cerebral arteriolar thickening, cerebral arteriolar cell proliferation, and hippocampal CA1 neuronal cell reduction (1024.9+/-20.6 versus 724.9+/-22.8 cells/mm2; P<0.01; n=7 to 10 in each group) in SHRSP by candesartan (P<0.05) than amlodipine. Salt loading increased superoxide and NADPH oxidase activity in brain cortex and hippocampus of SHRSP, and this increase was prevented by candesartan (P<0.01) but not amlodipine. Angiotensin II infusion, via AT1 receptor, directly increased brain superoxide by 1.8-fold (P<0.05; n=6 to 7 in each group) and impaired blood-brain barrier in salt-loaded SHRSP by 1.7-fold (P<0.05), and this increase in brain superoxide and blood-brain barrier impairment was prevented by tempol as well as candesartan. Excess salt, via oxidative stress, accelerates stroke, and angiotensin II, via AT1 receptor, plays a pivotal role in brain superoxide production of SHRSP by excess salt.
    Stroke 05/2005; 36(5):1083-8. DOI:10.1161/01.STR.0000163084.16505.e3 · 6.02 Impact Factor
  • Nippon rinsho. Japanese journal of clinical medicine 04/2005; 63 Suppl 3:17-21.
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    ABSTRACT: Vascular endothelial growth factor (VEGF) and Angiopoietin-2 (Ang-2) play complementary roles in the process of vascular remodeling. Therefore, this study was designed to examine an interaction between VEGF and Ang-2 in asthmatic airways. VEGF, Ang-2, and hepatocyte growth factor (HGF) levels in induced sputum obtained from 17 asthmatic patients and 10 normal control subjects were examined. Eight weeks of inhaled beclomethasone dipropionate (BDP) therapy (800 microg/day) was administered to all asthmatic patients, and sputum induction was repeated. VEGF, Ang-2, and HGF levels in induced sputum were significantly higher in asthmatic patients than in control subjects. Ang-2 levels were significantly correlated with VEGF levels but not with HGF levels. We also found that there was a significant correlation between airway vascular permeability index and VEGF levels but not HGF levels. In addition, VEGF/Ang-2 ratio in asthmatic patients was significantly higher than that in control subjects, and it was significantly correlated with airway vascular permeability index. After inhaled BDP therapy, VEGF levels were significantly decreased, but Ang-2 levels did not change. Therefore, VEGF/Ang-2 ratio after BDP therapy was markedly decreased to the same level as in the control subjects. Our findings suggest that interaction between VEGF and Ang-2 in asthmatic airways may exist and that high VEGF/Ang-2 ratio may be responsible for increased airway microvascular permeability. In addition, inhaled glucocorticoids therapy may reduce airway vascular permeability and remodeling via VEGF/Ang-2-dependent mechanism.
    Journal of Asthma 04/2005; 42(2):141-6. DOI:10.1081/JAS-51346 · 1.83 Impact Factor
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    ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1) has been implicated as a contributing risk factor for cardiovascular disease. However, little is known about molecular mechanisms of cardiac PAI-1 gene expression. To elucidate these mechanisms, dominant negative mutants of c-Jun NH(2)-terminal kinase (JNK), p38MAPK, apoptosis signal-regulating kinase-1 (ASK-1) and c-Jun were overexpressed in rat neonatal ventricular cardiac myocytes and fibroblasts by adenovirus vector to abrogate the activation of the corresponding endogenous proteins. One hundred nmol/l of angiotensin II significantly enhanced the JNK and p38MAPK activities of cardiomyocytes (2.3-fold and 1.9-fold, P < 0.05) and fibroblasts (3.2-fold and 2.5-fold, P < 0.05). At 3 h after stimulation, angiotensin II was found to have significantly increased PAI-1 mRNA, by 5.2-fold in cardiomyocytes and by 9.7-fold in fibroblasts. Dominant negative mutants of JNK, ASK-1 and c-Jun significantly inhibited PAI-1 mRNA expression and protein synthesis in both cardiomyocytes and fibroblasts, whereas a dominant negative mutant of p38MAPK did not change this expression. Moreover, a dominant negative mutant of JNK also significantly prevented the induction of PAI-1 mRNA expression by 100 nmol/l endothelin-1 and 10 micromol/l phenylephrine. In conclusion, G-protein-coupled receptor agonist-induced PAI-1 expression is partially mediated through JNK activation.
    Journal of Molecular and Cellular Cardiology 04/2005; 38(4):583-92. DOI:10.1016/j.yjmcc.2005.01.008 · 5.22 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) has been reported to be associated with cardiomyopathy. However, the mechanism of cardiomyopathy in chronic HCV infection is still unclear. Therefore, we investigate the development of cardiomyopathy in mice transgenic for the HCV-core gene. After the age of 12 months, mice developed cardiomyopathy that appeared as left ventricular dilatation, and systolic and diastolic dysfunction assessed by Doppler echocardiography. Histologically, hypertrophy of cardiomyocytes, cardiac fibrosis, disarray and scarcity of myofibrils, vacuolization and deformity of nuclei, myofibrillar lysis, streaming of Z-bands, and an increased number of bizarre-shaped mitochondria were found in HCV-core transgenic mice. These histological changes are just consistent with cardiomyopathy. In conclusion, the HCV-core protein directly plays an important role in the development of cardiomyopathy.
    Circulation Research 03/2005; 96(2):148-50. DOI:10.1161/01.RES.0000154263.70223.13 · 11.09 Impact Factor

Publication Stats

6k Citations
938.29 Total Impact Points

Institutions

  • 1982–2014
    • Osaka City University
      • • Department of Pharmacology
      • • Graduate School of Medicine
      • • Department of Gastroenterology
      Ōsaka, Ōsaka, Japan
  • 2004
    • The University of Tokyo
      • Department of Pharmaceutical Sciences
      白山, Tōkyō, Japan
  • 2003
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan