Biomedical subjects

Satoshi Ogawa

Publications and source records attributed to Satoshi Ogawa.

At least 55 records · Page 3Linked to original sources

PubMed2005

Relation of stent overexpansion to the angiographic no-reflow phenomenon in intravascular ultrasound-guided stent implantation for acute myocardial infarction.

The angiographic no-reflow phenomenon is observed in some patients during stent implantation for acute myocardial infarction (AMI). We attempted to clarify the influence of stent overexpansion and plaque morphology on the angiographic no-reflow phenomenon in AMI patients who underwent intravascular ultrasound (IVUS)-guided stent implantation. We assessed the thrombolysis in myocardial infarction (TIMI) flow grade in the coronary angiographic findings, and quantitative and qualitative IVUS findings, in a total of 90 patients who underwent IVUS-guided stenting for AMI. The patients were divided into two groups according to the stent-to-artery ratio: overexpansion group (ratio > or =1.2) and non-overexpansion group (ratio <1.2). Angiographic no-reflow (defined as TIMI flow grade <3) in stent implantation was observed in 15 patients (17%). Angiographic no-reflow was more frequently observed in the overexpansion group than in the non-overexpansion group (32% vs 11%, P = 0.0312). Patients with no-reflow had more lipid pool-like images or fissure/dissection than those without. In the overexpansion group, a lipid pool-like image and fissure/dissection were more frequently observed in patients with no-reflow. The rate of target lesion revascularization (TLR) in the overexpansion group was significantly lower than that in the non-overexpansion group during the follow-up period (10% vs 18%, P = 0.0476), but the incidence of pump failure in the overexpansion group was higher than that in the non-overexpansion group during the hospital course (28% vs 14%, P = 0.0358). Stent overexpansion in AMI patients is related to a higher incidence of angiographic no-reflow, especially if the lesion has a lipid pool-like image or fissure/dissection, although there is a tendency for lower TLR.

Aged↗

PubMed2005

Carvedilol exerts more potent antiadrenergic effect than metoprolol in heart failure.

BACKGROUND: It is still uncertain whether or not there is a difference between metoprolol and carvedilol for the treatment of congestive heart failure. We attempted to determine the difference between the two beta-blockers in terms of their antiadrenergic effect during exercise in patients with heart failure and their efficacy based on the baseline plasma brain natriuretic peptide concentration. METHODS: Fifty-three patients with mild to moderate heart failure with a radionuclide left ventricular ejection fraction <40% received open label metoprolol or carvedilol in a randomized fashion. The increase in the heart rate normalized to the increase in the plasma norepinephrine concentration during exercise, was calculated as an index of adrenergic responsiveness during exercise. RESULTS: The increase in heart rate normalized by the increase in plasma norepinephrine concentration, decreased after the initiation of beta-blockers in the carvedilol group, but not in the metoprolol group. The change in cardiac function was more favorable for carvedilol than metoprolol in patients who exhibited a higher baseline brain natriuretic peptide concentration. CONCLUSIONS: Carvedilol exerts a more potent antiadrenergic effect than metoprolol during stress in patients with mild to moderate heart failure. Carvedilol appears to be more efficacious than metoprolol in patients who exhibit higher baseline brain natriuretic peptide concentrations. These differences should be kept in mind when selecting appropriate pharmacologic agents in the treatment of heart failure.

Adrenergic beta-Antagonists↗

PubMed2005

Temporal patterns of progression and regression of electrical and mechanical remodeling of the atrium.

OBJECTIVES: We evaluated serial changes of electrical and mechanical parameters of atrial remodeling in dogs subjected to rapid atrial pacing. BACKGROUND: Prolonged rapid atrial excitation causes electrical and mechanical remodeling, which contributes to persistence of atrial fibrillation and clot formation. However, the temporal relationship between these two types of atrial remodeling remains unknown. METHODS: In 8 dogs, rapid pacing at 400 ppm was continued for 14 days. The electrophysiologic and transesophageal echocardiographic studies were performed on the day before and after 2, 7, and 14 days of rapid pacing, then 1 and 7 days after the cessation of pacing. These were compared with sham-operated dogs (instrumented but not paced, n=6). RESULTS: With rapid pacing, there was an immediate shortening of the effective refractory period (ERP) and decreases in the transmitral atrial wave velocity (MAV) and the left atrial appendage emptying velocity (LAAV). In contrast, conduction velocity (CV) decreased and the left atrial appendage area (LAAA) increased progressively over 14 days. During the recovery, ERP, MAV, and LAAV returned to the baseline in 1 day, whereas CV and LAAA did in 7 days. ERP was highly positively correlated with LAAV (r=0.78, p<0.001) and MAV (r=0.73, p<0.001), while CV was negatively correlated only with LAAA (r=-0.58, p<0.001). CONCLUSIONS: Pacing-induced electrical and mechanical remodeling of the atrium exhibits divergent patterns of progression and regression such that changes of ERP and contractile function take place more rapidly than those of CV and atrial size.

Animals↗

PubMed2005

RA410/Sly1 suppresses MPP+ and 6-hydroxydopamine-induced cell death in SH-SY5Y cells.

Parkinson's disease is characterized by selective loss of dopaminergic neurons in the substantia nigra. However, its associated cell death mechanism remains unknown. 1-Methyl-4-phenil-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) cause dopaminergic neuronal cell death. Both are widely used to model PD. We investigated the role of a vesicle-transport-related protein, RA410/Sly1, in SH-SY5Y cells to clarify the mechanism of cellular adaptation to MPP+ and 6-OHDA-induced stress. Antisense RA410/Sly1 transformants treated with these toxins displayed reduced viability in comparison with viability of wild-type or RA410/Sly1 sense transformants. Electron microscopy analysis indicated that the ER in MPP+-treated antisense RA410/Sly1 transformants was rapidly disrupted in comparison to wild-type or sense RNA transformants. Cell death induced by MPP+ and 6-OHDA was suppressed in RA410/Sly1 sense transformants through suppression of caspase-2, -3 and -9 activation. These results suggest that RA410/Sly1 plays an important cytoprotective role in MPP+ and 6-OHDA-induced cellular perturbation.

1-Methyl-4-phenylpyridinium↗

PubMed2005

150-kDa oxygen-regulated protein attenuates myocardial ischemia-reperfusion injury in rat heart.

Early contractile dysfunction and the later death of cardiomyocytes are two major problems that can follow myocardial infarction or major cardiovascular surgery that demands ischemic arrest of the heart. Here, we found that 24 h of hypoxia and 1 h of reoxygenation induced the expression of the chaperone ORP150 in cultured rat cardiomyocytes. Inhibition of its induction using an adenovirus to express anti-sense ORP150 significantly enhanced the hypoxia-reoxygenation-induced cardiomyocyte death; cell death was reduced by overexpressing ORP150. Decreased levels of ORP150 expression also enhanced caspase-3 and -8 activation, cytochrome-c release, and DNA fragmentation, suggesting that this chaperone regulates apoptotic cell death. In contrast, increasing the expression of ORP150 in the cardiomyocytes had the opposite effect on the expression of these molecules. Moreover, apoptotic cell death initiated by myocardial ischemia-reperfusion (I/R) was significantly inhibited in vivo by transfecting an ORP150 expression plasmid into whole rat heart using the hemagglutinating virus of Japan (HVJ)-liposome method. Interestingly, ORP150 seemed to preserve calcium homeostasis in cardiomyocytes that underwent ischemia-reoxygenation in vitro. Calpain activity in the cardiomyocytes was enhanced by anti-sense ORP150 and suppressed by sense ORP150. Finally, we examined the functional recovery of rat hearts that overexpressed ORP150 or GFP protein and were subjected to I/R; we found that ORP150 preserved early contractile function after transient ischemia. Our results indicated cytoprotective roles for ORP150 in rat heart and suggested a therapeutic role for the protein both in preventing cardiomyocyte death and in preserving contractile function after ischemic damage.

Animals↗

PubMed2005

Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis.

Apoptosis of cardiomyocytes plays an important role in reperfusion injury following myocardial infarction. Conversely, interleukin-6 (IL-6)--a potent cytokine--inhibits myeloma cell apoptosis by activating GP130 through the IL-6 receptor (IL-6R). We hypothesized that the IL-6/soluble IL-6R complex can inhibit myocardial apoptosis, and limit infarct size in reperfused acute myocardial infarction. Anesthetized rats were randomly divided into five groups: sham, coronary occlusion and reperfusion rats administered IL-6/soluble IL-6R complex, IL-6 alone, soluble IL-6R (sIL-6R) alone, or a control vehicle. Rats were subjected to 30 min occlusion of the left coronary artery followed by 3 h reperfusion. After reperfusion, the hearts were excised. For detection and quantification of apoptosis, gel electrophoresis of extracted genomic DNA and TUNEL method of paraffin sections were performed. The percentage of the infarct area was measured using tetrazolium chloride staining. The cardiomyocyte apoptosis analysis revealed that apoptosis in the reperfused myocardium was inhibited only in the complex group. Furthermore, the percentage of the infarct area out of the area at risk was remarkably reduced in the complex group (23.8+/-1.8%), compared with that in the vehicle (37.9+/-3.7%), the IL-6 (40.7+/-1.0%), or the sIL-6R (37.5+/-2.4%) groups (P=0.0002). No significant differences were observed among the vehicle, IL-6, and sIL-6R groups. The IL-6/soluble IL-6 receptor complex inhibits cardiomyocyte apoptosis in reperfused acute myocardial infarction. It possibly reduces irreversible reperfusion injury.

Animals↗

PubMed2005

Cardiomyogenic potential of mesenchymal progenitors derived from human circulating CD14+ monocytes.

Previously, we reported a unique CD14+CD45+CD34+type I collagen+ cell fraction derived from human circulating CD14+ monocytes, named monocyte-derived mesenchymal progenitors (MOMPs). These primitive cells differentiate along mesenchymal lineages, including bone, cartilage, fat, and skeletal muscle. Here, we demonstrate that CD14+ monocytes generate MOMPs that differentiate into cardiomyocytes. MOMPs labeled with a fluorescent marker and co-cultivated with rat cardiomyocytes for 4 weeks expressed the cardiomyocyte-specific transcription factors Nkx2.5, GATA-4, eHAND, and MEF2 and the hematopoietic/monocytic markers CD45 and CD14 within 10 days and retained their proliferative capacity for up to 16 days. A subpopulation of MOMPs subsequently expressed the cardiomyocyte-specific markers micro-sarcomeric actinin, troponin I, and atrial natriuretic peptide on day 21. Furthermore, fluorescence-labeled, spontaneously beating cells that formed gap junctions with adjacent rat cardiomyocytes appeared in these cultures and these cells exhibited electrophysiological properties typical of ventricular myocytes. The co-cultivation of human MOMPs with rat GFP-tagged cardiomyocytes resulted in the generation of human cardiomyocytes lacking green fluorescent protein (GFP) staining, suggesting that our observations could not solely be explained by cell fusion. Our results demonstrate for the first time that human circulating CD14+ monocytes include progenitors capable of proliferating and differentiating along the cardiomyogenic lineage via their differentiation into MOMPs.

Animals↗

PubMed2005

Flow-independent myocardial ischemia induced by endothelin-1: an NADH fluorescence analysis.

The endothelin-1 (ET-1) is known to cause myocardial ischemia; however, whether this effect is entirely dependent on vasoconstriction is uncertain. The aim of this study was to characterize the myocardial ischemia after the intracoronary administration of endothelin-1, and compare it with that induced by coronary stenosis. In the left anterior descending coronary artery of 15 dogs, a mild inflow reduction (30%) was produced for 10 minutes using intracoronary endothelin-1 (46 +/- 33 pmol/min) or coronary stenosis. The hearts were rapidly cross-sectioned at short axial plane and freeze-clamped within 120 milliseconds using a specially developed device to visualize and quantify the area of ischemia (%IA) with NADH fluorescence photography. The %IA was larger in the endothelin-1 group than in the stenosis group (66 +/- 23 versus 18 +/- 18, P = 0.0005); furthermore, the ischemia was transmural in the ET-1 group, but limited to subendocardium in the stenosis group. ET-1 increased the coronary arterial resistance especially in subepicardial region and produced smaller ischemic foci in microcirculation. The mechanism of larger ischemia produced by ET-1 might depend on pro-ischemic effects on myocytes and vasoconstriction of the coronary microcirculation, predominantly in the subepicardium in vivo.

Animals↗

PubMed2005

Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation.

BACKGROUND: An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. As a defense mechanism, cells express ER stress inducible chaperons, such as oxygen-regulated proteins 150 (ORP150) and glucose-regulated proteins (GRPs). While ER stress is important in various diseases, a pathophysiologic role for ER stress in kidney disease remains elusive. Here we investigate expression of ER stress proteins in cultured rat podocytes as well as in our recently developed animal model of abnormal protein retention within the ER of podocytes (i.e., megsin transgenic rat). METHODS: The expression of ER stress inducible proteins (ORP150, GRP78, or GRP94) in cultured podocytes treated with tunicamycin, A23187, SNAP, hypoxia, or hyperglycemia, and the renal tissues or isolated glomeruli from megsin transgenic rats was analyzed by Western blotting analysis, immunohistochemistry, or confocal microscopy. RESULTS: Cultured podocytes demonstrated that treatment with tunicamycin, A23187, and SNAP, but not hypoxia or hyperglycemia, up-regulate expression of ER stress proteins. Extracts of isolated glomeruli from megsin transgenic rats reveal marked up-regulation of ER stress chaperones in podocytes, which was supported by immunohistochemical analysis. Confocal microscopy revealed that ER stress in podocytes was associated with cellular injury. Podocytes of transgenic rats overexpressing a mutant megsin, without the capacity for polymerization within the ER, do not exhibit ER stress or podocyte damage, suggesting a pathogenic role of ER retention of polymerized megsin. CONCLUSION: This paper implicates a crucial role for the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury.

Animals↗

PubMed2005

A new method for manufacturing cardiac cell sheets using fibrin-coated dishes and its electrophysiological studies by optical mapping.

We developed a novel simple method for making functional myocardial cell sheets that may be used as transplants. Polymerized human fibrin-coated dishes were prepared with fibrinogen monomers mixed with thrombin. Neonatal rat cardiomyocytes cultured on these dishes formed myocardial cell sheets within 4 days. These cell sheets were easily dissociated intact from the polymerized fibrin layer, because the fibrin had been digested by intrinsic protease. Two overlaid myocardial cell sheets exhibited synchronized spontaneous beating and captured artificial pacing. Optical mapping confirmed that the conduction of the action potential between two partially overlaid myocardial cell sheets was established, and the action potential propagated across the junction without any delay. Transplanted three-layered myocardial cell sheets exhibited strong spontaneous beating and showed well-differentiated striations and an increase in cell size. This simple method of cell sheet engineering may also be applicable for various other cell types.

Animals↗

PubMed2005

Combination of hTERT and bmi-1, E6, or E7 induces prolongation of the life span of bone marrow stromal cells from an elderly donor without affecting their neurogenic potential.

Murine bone marrow stromal cells differentiate not only into mesodermal derivatives, such as osteocytes, chondrocytes, adipocytes, skeletal myocytes, and cardiomyocytes, but also into neuroectodermal cells in vitro. Human bone marrow stromal cells are easy to isolate but difficult to study because of their limited life span. To overcome this problem, we attempted to prolong the life span of bone marrow stromal cells and investigated whether bone marrow stromal cells modified with bmi-1, hTERT, E6, and E7 retained their differentiated capability, or multipotency. In this study, we demonstrated that the life span of bone marrow stromal cells derived from a 91-year-old donor could be extended and that the stromal cells with an extended life span differentiated into neuronal cells in vitro. We examined the neuronally differentiated cells morphologically, physiologically, and biologically and compared the gene profiles of undifferentiated and differentiated cells. The neuronally differentiated cells exhibited characteristics similar to those of midbrain neuronal progenitors. Thus, the results of this study support the possible use of autologous-cell graft systems to treat central nervous system diseases in geriatric patients.

Aged↗

PubMed2005

Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice.

MMPs are implicated in LV remodeling after acute myocardial infarction (MI). To analyze the role of MMP-2, we generated MI by ligating the left coronary artery of MMP-2-KO and WT mice, the latter of which were administered orally an MMP-2-selective inhibitor or vehicle (TISAM). The survival rate was significantly higher in MMP-2-KO and TISAM-treated mice than in control WT mice. The main cause of mortality in control WT mice was cardiac rupture, which was not observed in MMP-2-KO or TISAM-treated mice. Control WT mice, but not MMP-2-KO or TISAM-treated mice, showed activation of the zymogen of MMP-2, strong gelatinolytic activity, and degradation of ECM components, including laminin and fibronectin, in the infarcted myocardium. Although infarcted cardiomyocytes in control WT mice were rapidly removed by macrophages, the removal was suppressed in MMP-2-KO and TISAM-treated mice. Macrophage migration was induced by the infarcted myocardial tissue from control WT mice and was inhibited by treatment of macrophages with laminin or fibronectin peptides prior to migration assay. These data suggest that inhibition of MMP-2 activity improves the survival rate after acute MI by preventing cardiac rupture and delays post-MI remodeling through a reduction in macrophage infiltration.

Animals↗

PubMed2005

Emergency treatment with nifekalant, a novel class III anti-arrhythmic agent, for life-threatening refractory ventricular tachyarrhythmias: post-marketing special investigation.

BACKGROUND: Because class I anti-arrhythmic drugs sometimes suppress cardiac function caused by their negative inotropic effects, they are not adequate for use in patients with severe heart failure, even as emergency treatment for life-threatening ventricular tachyarrhythmias (ventricular tachycardia (VT)/ventricular fibrillation (VF)). METHODS AND RESULTS: An objective evaluation committee re-evaluated the effect of nifekalant in 191 patients with refractory VT/VF. The attack termination was achieved in 45 out of 93 patients (48.4%). Nifekalant was administered to 39 patients with direct-current (DC) shock-resistant VT/VF and directly terminated VT/VF in 9 patients. In 15 of the remaining 29 patients (51.7%), VT/VF was successfully cardioverted by additional DC shock after nifekalant administration. Prevention of recurrence was achieved in 60 out of 99 patients (60.6%). Corrected QT interval (QTc) was significantly prolonged after initial administration of nifekalant (0.463+/-0.056 to 0.504 +/-0.072), and during maintenance infusion (0.470 +/-0.056 to 0.547+/-0.070). As an adverse reaction, excess prolongation of QTc was noted in 11 patients including 3 patients with torsades de pointes. Hemodynamic parameters tended to improve after maintenance infusion of nifekalant. CONCLUSION: Nifekalant is effective and useful for life-threatening refractory ventricular tachyarrhythmias, although careful observation of the QT interval is required.

Aged↗

PubMed2005

Multicenter survey on the validity of the CD-ROM guideline for antiarrhythmic drug therapy produced by the Japanese Circulation Society and the Japanese Society on Electrocardiology: preliminary report of the survey of the Japanese guideline for Arrhythmia Management By Individual Therapy (J-GAMBIT).

BACKGROUND: A multicenter investigational survey (Japanese Guideline for Arrhythmia Management By Individual Therapy) was conducted to evaluate the validity of using CD-ROM guidelines vs physician choice for the selection of antiarrhythmic drugs. METHODS AND RESULTS: Patients with paroxysmal atrial fibrillation (PAF, n=274) or premature ventricular contractions (PVC, n=216) were enrolled. The rate of concordance for drug selection between the treating physician and the CD-ROM was 216 of 274 patients (78.8%) with PAF. Of these, 168 (61.3%) were concordant for first-line agents and the remaining 48 (17.5%) were concordant for second-line agents. The concordance for the treatment of PVC was 154/216 cases (71.3%). Of these, 106 (49.1%) were concordant for first-line agents and the remaining 48 (22.2%) were concordant for second-line agents. Nonconcordance for PAF therapy was more likely to occur for patients with underlying heart disease (p<0.05), depressed cardiac function (p<0.001), and with more frequent ECG abnormalities and renal dysfunction. These differences were not seen in patients with PVC. CONCLUSION: The CD-ROM guidelines appear to be valid in the selection of antiarrhythmic drugs for both PAF and PVC, but their usefulness is influenced by the patient's clinical characteristics.

Aged↗

PubMed2005

Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol.

BACKGROUND: Epoprostenol (prostaglandin I(2)) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option. METHODS AND RESULTS: The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9+/-5 mmHg before and significantly increased to 13+/-3 mmHg after epoprostenol administration (p < 0.05). One patient died and the other 5 patients received oral sildenafil. The mRA of 12+/-4 mmHg (value before sildenafil) improved to 8+/-5 mmHg after sildenafil administration. Three patients were classified in the NYHA functional class 4 and improved to class 3, and 2 patients were in class 3 and remained in the same class after the addition of sildenafil. CONCLUSIONS: In patients with severe PPH refractory to epoprostenol treatment, additional oral sildenafil can improve pulmonary hemodynamics and symptoms. The combination therapy of epoprostenol and sildenafil is a new medical treatment to attempt before progressing to lung transplantation for patients with PPH refractory to epoprostenol.

Administration, Oral↗

PubMed2005

Link between SCN5A mutation and the Brugada syndrome ECG phenotype: simulation study.

BACKGROUND: The specific changes in the gating kinetics of the sodium current (I(Na)) responsible for its phenotype have remained to be elucidated. In the present study the effect of changes in the gating kinetics of I(Na) on early repolarization (ER) and initiation of phase 2 reentry (P2R) were evaluated in a theoretical epicardial ventricular fiber model. METHODS AND RESULTS: Miyoshi-I(CaL) was incorporated into the modified Luo-Rudy dynamic (LRd) model. Dispersion at Ito-density was set within a theoretical fiber composed of serially arranged epicardial cells with gap junctions. The following changes in I(Na) kinetics were made: (1) a-10 mV shift in steady-state inactivation, (2) a+10 mV shift in steady-state activation curve, (3) a small inactivation time constant (DEC); P2R and ER were observed. A conduction disturbance within the fiber was simulated and only when the I(Na)-density was decreased did DEC, especially, show a marked increase in the likelihood of causing ER and P2R. Conduction disturbance significantly increased the likelihood causing ER or P2R. CONCLUSIONS: In this one-dimension model with Ito-density dispersion, DEC-I(Na) precipitates I(Na)-blocker inducible ER. This suggests that the characteristic ST-segment elevation in the Brugada syndrome with SCN5A mutation can be interpreted in part by DEC-I(Na). Concomitant conduction disturbance may be required to cause P2R at physiological Ito density.

Arrhythmias, Cardiac↗

PubMed2005

Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension.

STUDY OBJECTIVE: In these days, it was reported that bone marrow (BM) cells might take part in the remodeling of some systemic vascular diseases; however, it remains unknown whether the BM cells were involved in the vascular remodeling of pulmonary arteries and the progression of pulmonary hypertension (PH). The purpose of this study was to investigate whether BM-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced PH. MATERIALS AND METHODS: To investigate the role of BM-derived cells, we transplanted the whole BM of enhanced green fluorescent protein (GFP)-transgenic mice to the lethally irradiated syngeneic mice (n = 30). After 8 weeks, chimera mice were exposed to consistent hypoxia using a hypoxic chamber (10% O(2)) for up to 4 or 8 weeks (10 mice per group). After hemodynamics and the ratio of right ventricular (RV) weight to left ventricle (LV) weight, RV/(LV + septum [S]), were measured, histologic and immunofluorescent staining were performed. RESULTS: BM-transplanted mice showed a high chimerism (mean [+/- SEM], 91 +/- 2.3%). RV systolic pressure and the RV/(LV + S) ratio increased significantly with time in PH mice, indicating RV hypertrophy. Marked vascular remodeling including medial hypertrophy and adventitial proliferation was observed in the pulmonary arteries of PH mice. Strikingly, a number of GFP(+) cells were observed at the pulmonary arterial wall, including the adventitia, in hypoxia-induced PH mice, while very few cells were observed in the control mice. Metaspectrometer measurements using confocal laser scanning microscopy confirmed that this green fluorescence was produced by GFP, suggesting that these GFP(+) cells were mobilized from the BM. Most of them expressed alpha-smooth muscle actin, a smooth muscle cell, or myofibroblast phenotype, and contributed to the pulmonary vascular remodeling. A semiquantitative polymerase chain reaction of the GFP gene revealed that the BM-derived GFP-positive cells in the PH group were observed more than eightfold as often compared with the control mice. CONCLUSION: The BM-derived cells mobilize to the hypertensive pulmonary arteries and contribute to the pulmonary vascular remodeling in hypoxia-induced PH mice.

Animals↗

PubMed2005

The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.

To determine the role of the endoplasmic reticulum (ER) in diabetes, Akita mice, a mouse model of type 2 diabetes, were mated with either heterozygous knockout mice or two types of transgenic mice of 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone located in the ER. Systemic expression of ORP150 in Akita mice improves insulin intolerance, whereas the exclusive overexpression of ORP150 in pancreatic beta-cells of Akita mice did not change their glucose tolerance. Both an insulin tolerance test and hyperinsulinemic-euglycemic clamp revealed that ORP150 enhanced glucose uptake, accompanied by suppression of oxidized protein. Furthermore, ORP150 enhanced the insulin sensitivity of myoblast cells treated with hydrogen peroxide. These data suggest that ORP150 plays an important role in insulin sensitivity and is a potential target for the treatment of diabetes.

Animals↗