Yoshihide Mitani - Academia.edu (original) (raw)

Papers by Yoshihide Mitani

American Journal of Physiology-lung Cellular and Molecular Physiology, Mar 15, 2015

It remains unknown whether current disease-targeting therapy can histologically reverse obstructi... more It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3-5 wk (early study) or during 5-8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67ϩ lesions in both studies, macitentan increased the proportion of cleaved caspase 3ϩ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD. pulmonary hypertension; endothelin; pathology; apoptosis PULMONARY ARTERIAL HYPERTENSION (PAH) is a progressive obstructive vasculopathy that leads to increased pulmonary vascular resistance, right ventricular failure, and premature death. This disorder is characterized by an imbalance in proliferation/ apoptosis, a resistance to apoptosis in vascular cells, and later appearance of fibrotic change in the lesions (6). Recently a significant body of evidence, including the results of metaanalyses, showed that drugs targeting one or more of three principal pathways, the endothelin, nitric oxide, and prostacyclin pathways, can improve clinical and hemodynamic parameters and even the survival of patients with PAH (10). However, it remains unknown whether any current PAH-specific

Frontiers in Pharmacology, 2016

Involvement of CCDC80 in PAH model and found increased expression in the hypertrophied media and ... more Involvement of CCDC80 in PAH model and found increased expression in the hypertrophied media and adventitia of the pre-acinar pulmonary arteries (PAs) and in the thickened intima, media, and adventitia of the obstructed intra-acinar PAs. These results suggest that increased expression of CCDC80 may be involved in the pathogenesis of PAH, potentially by modulating the expression of endothelin-1 and COL1A1.

Background-Coronary artery lesions (CALs) late after Kawasaki disease were characterized by endot... more Background-Coronary artery lesions (CALs) late after Kawasaki disease were characterized by endothelial dysfunction and low-grade inflammation, surrogate markers for atherosclerosis. We tested the hypothesis that CALs in patients long after Kawasaki disease are accompanied by atheroma-like features, as assessed by virtual histology-intravascular ultrasound, a new method to assess coronary plaque composition and morphology in vivo. Methods and Results-Virtual histology-intravascular ultrasound was performed in 13 Japanese Kawasaki disease patients (median age, 18.3 years; interquartile range, 16.9 to 23.3 years) an interval after Kawasaki disease (median, 15.9 years; interquartile range, 14.3 to 21.9 years). We investigated 6 sites with localized stenosis, 15 sites with an aneurysm, 29 sites with a regressed aneurysm, and 50 sites with a normal coronary segment. Plaque components were categorized into 4 parts: fibrous, fibrofatty, necrotic core, and dense calcium areas. Qualitatively...

The Journal of Thoracic and Cardiovascular Surgery, 2008

Objectives: A novel hemagglutinating virus of Japan (HVJ, a murine parainfluenza virus) envelope ... more Objectives: A novel hemagglutinating virus of Japan (HVJ, a murine parainfluenza virus) envelope vector system, in which DNA is incorporated into an inactivated viral particle deprived of its genome, was recently developed as a ready-to-use vector for gene therapy. We therefore investigated whether intratracheal gene transfer using this vector can induce transgene expression in the lung and whether atrial natriuretic peptide gene transfer ameliorates pulmonary hypertension in rats. Methods: Rats transfected intratracheally with b-galactosidase vector, atrial natriuretic peptide vector, or mock vector were investigated for the evaluation of b-galactosidase expression, atrial natriuretic peptide mRNA expression, and inflammatory cell infiltration. Rats were divided into 5 treatment groups (n 5 73): normoxic rats treated intratracheally with mock vector or atrial natriuretic peptide gene and chronic hypoxic rats treated similarly with mock vector, atrial natriuretic peptide, or a reporter gene, b-galactosidase. Pulmonary hypertension and transfected gene expression were evaluated. Results: b-Galactosidase gene transfer induced its intense enzymatic activity in bronchial and alveolar epithelial cells but not in other organs in normoxic rats. Transfected lungs were not associated with inflammatory cell infiltration. Atrial natriuretic peptide gene transfection inhibited pulmonary hypertension, which is associated with its mRNA expression in the lungs. Indices of right ventricular hypertrophy and pulmonary vascular diseases induced by chronic hypoxia were significantly but incompletely ameliorated. Conclusions: HVJ-envelope vector is an efficient, relatively safe, and ready-to-use gene delivery system for pulmonary vascular diseases. Atrial natriuretic peptide gene transfer to lungs by using this vector could be a promising therapeutic approach against pulmonary hypertension.

Thorax, 1999

Mast cells are known to be involved in various types of tissue remodelling but their role in pulm... more Mast cells are known to be involved in various types of tissue remodelling but their role in pulmonary hypertension is still poorly understood. Two subtypes of mast cells have recently been identified by demonstrating one protease, chymase. This enzyme might be implicated in vascular remodelling. The changes in mast cells in lung tissue from three patients with primary or secondary pulmonary hypertension were therefore investigated. Compared with tissue from four control subjects the number of mast cells in the three patients was markedly increased, which suggests that chymase containing mast cells are involved in tissue remodelling accompanied by fibrotic changes in primary and secondary pulmonary hypertension.

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The FASEB Journal, 2000

Nitric oxide (NO) reduces the severity of pulmonary vascular disease in rats as do elastase inhib... more Nitric oxide (NO) reduces the severity of pulmonary vascular disease in rats as do elastase inhibitors. We therefore hypothesized that NO inhibits elastase by suppressing mitogen-activated protein kinases that trans-activate AML1B, a transcription factor for elastase. We used cultured pulmonary artery smooth muscle cells in which serum-treated elastin (STE) induces a > threefold increase in elastase activity as evaluated by solubilization of [ 3 H]-elastin. NO donors (SNAP and DETA NONOate) inhibited elastase in a dose-dependent manner as did a cGMP mimetic (8-pCPT-cGMP). SNAP inhibition of elastase was reversed by coadministration of a cGMP-PKG inhibitor (Rp-8-pCPT-cGMP). The STE-induced increase in phospho-ERK was suppressed by NO donors and the cGMP mimetic, and reversed by cGMP-PKG inhibitor, as was expression of AML1B and DNA binding in nuclear extracts. A concomitant increase in p38 phosphorylation was also inhibited by SNAP, but whereas MEK inhibitor (PD98059) suppressed elastase and AML1B-DNA binding, a p38 inhibitor (SB202190) did not. Our study uniquely links NO with inhibition of elastasedependent matrix remodeling in vascular disease by suggesting a cGMP-PKG-related mechanism suppressing ERK-mediated partitioning of AML1B in nuclear extracts.-Mitani, Y., Zaidi, S. H. E., Dufourcq, P., Thompson, K., Rabinovitch, M. Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP-mediated suppression of ERK phosphorylation and AML1B nuclear partitioning.

The Journal of Thoracic and Cardiovascular Surgery, 2007

Journal of the American College of Cardiology, 1998

This study sought to assess the endothelial function of long-term coronary artery lesions in pati... more This study sought to assess the endothelial function of long-term coronary artery lesions in patients with Kawasaki disease (KD). Background. The vascular function of the coronary arteries in children with long-term KD remains uncertain. We report our findings of the vascular response of the coronary arteries to intracoronary injection of acetylcholine (ACh) in patients with KD. Methods. A total of 35 patients (25 patients with KD and 10 control subjects) were examined using coronary angiography. Individual arteries were divided into four groups according to the type of the coronary artery lesion: group 1 consisted of 25 sites with regressed aneurysms. These aneurysms had developed in the acute stage but had subsequently regressed and demonstrated normal findings on the follow-up coronary angiogram. Group 2 consisted of 24 sites with persistent aneurysms. Group 3 involved 60 angiographically normal sites in the same patients as those in group 1 or 2. Group 4 consisted of 30 sites in control subjects who had congenital heart disease with normal coronary arteries. During coronary angiography we infused 15 g of ACh chloride into the coronary artery. The lumen diameters were measured using a cine videodensitometric analyzer to study the distensibility of the coronary artery wall. Results. The mean (؎SD) change in diameter was an increase of 11.71 ؎ 12.34% in group 3 (coronary arteries without lesions in patients with KD) and 12.21 ؎ 9.71% in the control group, demonstrating marked vasodilation in both groups. In contrast, the changes in the regressed aneurysms of group 1 and in the persistent aneurysms of group 2 were ؊2.65 ؎ 12.12% and ؊0.08 ؎ 6.51%, respectively, demonstrating no change or mild vasoconstriction. The change in groups 1 and 2 was significantly less than that in group 3 or in the control group. Group 3 showed no significant difference from the control group. Conclusions. These findings suggest that long-term coronary artery lesions, even after aneurysm regression, may have impaired endothelial function. A long-term follow-up study for those patients is essential.

Journal of Cardiovascular Pharmacology, 2001

To investigate the effects of endothelin blockade initiated immediately after the onset of myocar... more To investigate the effects of endothelin blockade initiated immediately after the onset of myocardial infarction on survival and left ventricular remodeling, treatment with the nonselective receptor antagonist TAK-044 (n ‫ס‬ 22) or saline (n ‫ס‬ 19) for 3 weeks was initiated immediately after coronary ligation in rats. The 24-h survival rate was significantly lower in the TAK-044 group than in the saline group. The systolic blood pressure 24 h after the onset of myocardial infarction was similar in the saline and TAK-044 groups, although it was significantly lower in the TAK-044 group during the 3-week protocol. Heart weight/tibial length was significantly increased in the TAK-044 group compared with the saline group. As all deaths in the TAK-044 group occurred within 24 h after myocardial infarction, we performed additional experiments using a separate group of rats 12-16 h after myocardial infarction. Plasma and myocardial endothelin-1 levels were significantly increased, and a bolus injection of TAK-044 significantly reduced left ventricular dP/dt max in these rats that had had a myocardial infarction compared with sham-operated rats. Endothelin receptor blockade initiated immediately after the onset of myocardial infarction may deteriorate acute-phase survival and left ventricular remodeling. Inhibition of the positive inotropic action of endothlin-1 may partially explain the increased 24-h mortality.

Circulation, 2005

Background— Coronary sequelae that persist after Kawasaki disease (KD) have been associated with ... more Background— Coronary sequelae that persist after Kawasaki disease (KD) have been associated with obstructive changes of the lesions and coronary vascular events in adolescents and young adults. However, little is known about the association between sequelae late after KD and inflammatory markers, which are potential mediators and markers for atherogenesis. Methods and Results— Cross-sectional study was performed to test the hypothesis that coronary sequelae are associated with elevated levels of inflammatory markers in patients late after KD (mean time interval after the onset, 10 years, 10 months). Levels of high-sensitivity C-reactive protein (CRP), serum amyloid-A (SAA), interleukin-6, and soluble intercellular adhesion molecule-1 were measured in the 4 groups (n=80): the referent group (n=15) and KD subgroups with normal coronary arteries from the onset (n=27); with regressed aneurysms (n=18); and with coronary artery lesions, such as persistent aneurysms, stenosis, and occlusio...

Chest, 2007

Background: Pulmonary hypertension (PH) is a fatal disorder that is associated with structural ch... more Background: Pulmonary hypertension (PH) is a fatal disorder that is associated with structural changes and inflammatory responses in the pulmonary vasculature. Nuclear factor (NF)-B is a key transcription factor that is involved in the tissue remodeling mediated by inflammatory and fibroproliferative responses. However, the contribution of NF-B-mediated inflammatory pathways to the development of PH is unknown. Methods: We therefore investigated whether NF-B activation and the expression of a downstream product vascular cell adhesion molecule (VCAM)-1 is associated with pulmonary vascular diseases in rats that have been injected with the toxin monocrotaline (MCT), and whether a NF-B inhibitor, pyrrolidine dithiocarbamate (PDTC), ameliorates such diseases in rats. Results: VCAM-1 expression and the nuclear localization of the p65 subunit of NF-B, as analyzed immunohistochemically, was significantly up-regulated in the endothelium of diseased vessels on the days 8 to 22 (p < 0.05). Next, 39 rats were divided into three groups (rats injected with MCT and treated with saline solution or PDTC, and controls similarly treated with saline solution). Compared to controls, MCT treatment increased the mean (؎ SE) pulmonary artery pressure (31.2 ؎ 1.4 mm Hg [p < 0.05] vs 22.8 ؎ 0.9 mm Hg, respectively), which was reduced by PDTC treatment (24.3 ؎ 1.2 mm Hg; p < 0.05). Indexes of right ventricular hypertrophy and pulmonary vascular diseases induced by MCT were similarly inhibited (p < 0.05), which was associated with the suppression of VCAM-1 expression and macrophage infiltration. Conclusions: We concluded that the NF-B nuclear localization and VCAM-1 expression is temporally and spatially associated with the development of MCT-induced PH in rats, which was ameliorated by administering a NF-B inhibitor, PDTC.

Journal of applied physiology (Bethesda, Md. : 1985), 2002

Dexfenfluramine (Dex), an appetite suppressant and serotonin reuptake inhibitor, is associated wi... more Dexfenfluramine (Dex), an appetite suppressant and serotonin reuptake inhibitor, is associated with pulmonary vascular disease (PVD) in some patients. The variability might be related to undetermined genetic abnormalities interacting with factors such as gender, weight loss, and vascular injury. We, therefore, assessed the effect of Dex (5 mg. kg(-1). day(-1)) in female obese rats, designated JCR:LA-cp or cp/cp; in lean rats, designated (+/?); and in normal Sprague-Dawley (S-D) rats under control conditions or after endothelial injury induced by monocrotaline (60 mg/kg). Pulmonary arterial pressure, right ventricular hypertrophy, percent medial wall thickness of muscular arteries, and muscularization of peripheral arteries were assessed as indexes of PVD. Although Dex reduced weight gain in cp/cp and S-D rats (P < 0.05 for both), it did not cause PVD. Moreover, PVD in S-D rats after monocrotaline injection was paradoxically ameliorated by Dex (P < 0.05) despite induction of pu...

Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension, 2020

In Japan, we have a unique experience with pulmonary arterial hypertension (PAH): mandatory elect... more In Japan, we have a unique experience with pulmonary arterial hypertension (PAH): mandatory electrocardiography (ECG) screening in apparently healthy school children and lung biopsy study in infants with congenital heart disease and atypical PAH. Our recent nationwide survey demonstrated that the school ECG screening in Japan detects a substantial pediatric IPAH population that is associated with already established PH but without apparent right heart failure; early treatment in PAH patients was associated with better outcomes. Our lung biopsy study in small infants with atypical CHD-PAH in a single institute showed that microscopic respiratory disease was associated with the development of severe PH, which is unexplained by CHD but is reversible in acute vasodilator testing. We presented some experimental data supporting the benefit in initiating early treatment in PAH and targeting at-risk population from the perinatal period.

Respiratory Research

Background Patients with pulmonary arterial hypertension (PAH) carrying bone morphogenetic protei... more Background Patients with pulmonary arterial hypertension (PAH) carrying bone morphogenetic protein receptor type 2 (Bmpr2) mutations present earlier with severe hemodynamic compromise and have poorer survival outcomes than those without mutation. The mechanism underlying the worsening clinical phenotype of PAH with Bmpr2 mutations has been largely unaddressed in rat models of pulmonary hypertension (PH) because of the difficulty in reproducing progressive PH in mice and genetic modification in rats. We tested whether a clinically-relevant Bmpr2 mutation affects the progressive features of monocrotaline (MCT) induced-PH in rats. Methods A monoallelic single nucleotide insertion in exon 1 of Bmpr2 (+/44insG) was generated in rats using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9, then PH, pulmonary vascular disease (PVD) and survival after MCT injection with or without a phosphodiesterase type 5 inhibitor, tadalafil, administration we...

Journal of Experimental Medicine, 2014

Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal dis... more Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34–PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepre...

American journal of physiology. Lung cellular and molecular physiology, Jan 15, 2015

The Annals of Thoracic Surgery, 2008

during cardioplegia, the retrograde route is proposed. However, we avoided inserting retrograde c... more during cardioplegia, the retrograde route is proposed. However, we avoided inserting retrograde cardioplegia cannulas before the cardiopulmonary bypass due to the fragility of the dilated, thin coronary sinus. We applied antegrade cardioplegic perfusion together with digital closure of the fistula as previously described [7]. During cardioplegic infusion, in case of a fistula from the coronary arterial system to the coronary venous system, pressure inside the system would be too high and would perforate the thin coronary system. Surgical treatment should aim at closing the shunt and preserving the natural myocardial perfusion. Wauthy and colleagues [8] reported the successful ligation of a smaller fistula in a younger patient. Leaving the large segments of coronary vessels intact may induce thromboembolism. This is why we resected the whole aneurysmal segment and completed it with the bypassing of the posterior descending branch in our case. Although the right coronary main body expanded too much, there were not any remarkable branches worth bypassing except the posterior descending coronary artery. When we opened the aneurysmal RCA entirely, during selective left coronary antegrade cardioplegic infusion, all small acute marginal branches excessively bleeded retrograde. After dividing all marginal branches, we resected the body of the right coronary artery prior to the posterior descending coronary artery. The right coronary artery ostium on the aorta was repaired directly with a 3/0 nylon suture. After ligation of the coronary fistula hole over the coronary sinus, the exceedingly (2.5 cm) large coronary sinus was reduced and repaired with a continuous suture to avoid coronary sinus thrombosis. Resection of the aneurysmal RCA should prevent further thrombosis in the dilated segment and embolus to the acute marginal branches. Complete resection of the right coronary aneurysm and distal division of a fistula at the coronary sinus emergence is the basis of this procedure, unlike the previous publications. We conclude that in coronary artery aneurysm with coronary sinus fistula, the surgical strategy should be carefully planned. A fistula must be manually compressed while infusing cardioplegic solution. To identify and securely control the coronary origin of the fistula, the possible presence of "en cascade" aneurysms should be excluded. Complete aneurysmal coronary artery resection can be applied to avoid relapses and further embolic potential. Revascularization of the remarkable branches is essential for an enlarged myocardium.