永井 良三

A novel murine model of aging (kl/kl mice) has been developed by in vivo mutagenesis. We analyzed endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from 6- to 9-week old wild-type (+/+) and heterozygous (kl/+) klotho mice. The aortas of kl/+ mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) compared to +/+ mice. The response to sodium nitroprusside was unaltered in kl/+ mice. The contraction in response to norepinephrine was augmented by treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) to a greater extent in +/+ mice than in kl/+ mice. Treatment with L-NAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD. NO metabolites (NO2- and NO3-) and cGMP concentrations in the urine were significantly reduced in kl/+ mice compared to +/+ mice. However, the urinary excretion of 6-keto-prostaglandin F1alpha was unaltered. There was little immunostaining for NO synthase and vascular endothelial growth factor (VEGF) in the aorta of kl/+ mice. No immunostaining for NO synthase was noted in the aorta of kl/kl mice. The expression of the klotho gene product may have a role in the regulation of VEGF expression and is tightly linked to endothelial release of NO.

BACKGROUND/AIMS: We previously showed that the mesangial expression of nonmuscle-type myosin heavy chain, SMemb, was related to glomerular sclerosis. Although angiotensin II (AII) is known to promote the glomerular accumulation of extracellular matrix and sclerosis, the effect of AII on the mesangial expression of SMemb is unknown. Thus, we investigated the effect of AII on the mesangial expression of SMemb and synthesis of fibronectin. METHODS: We continuously administered AII to Sprague-Dawley rats with subcutaneous osmotic minipumps for 14 days. Control animals received normal saline instead. The effects of oral administration of an AII type 1 (AT1) receptor antagonist, candesartan cilexetil, and a vasodilator, hydralazine, were also examined. RESULTS: Semiquantitative immunohistochemical evaluation and Western blot analysis showed that AII significantly enhanced glomerular expression of SMemb (0.87 +/- 0.33 vs. 0.40 +/- 0.19 for immunohistochemical grading, p < 0.05; 2.55 +/- 0.88 vs. 1.16 +/- 0.75 for Western blot analysis, p < 0.05). Glomerular fibronectin was also increased in AII-administered rats (301.7 +/- 206.8 ng/5 microg protein vs. 95.8 +/- 81.3 ng/5 microg protein, p < 0.05). Candesartan cilexetil attenuated these effects. On the other hand, hydralazine did not change the glomerular expression of SMemb enhanced by AII administration. CONCLUSION: All induced a phenotypic alteration in mesangial cells, enhanced the mesangial expression of SMemb and stimulated the fibronectin synthesis. These results suggest that the mesangial expression of SMemb is related to glomerular matrix accumulation and that AII mediates both mesangial processes via AT1 receptors.

Background/Aims: We previously showed that the mesangial expression of nonmuscle-type myosin heavy chain, SMemb, was related to glomerular sclerosis. Although angiotensin 11 (All) is known to promote the glomerular accumulation of extracellular matrix and sclerosis, the effect of All on the mesangial expression of SMemb is unknown. Thus, we investigated the effect of All on the mesangial expression of SMemb and synthesis of fibronectin. Methods: We continuously administered All to Sprague-Dawley rats with subcutaneous osmotic minipumps for 14 days. Control animals received normal saline instead. The effects of oral administration of an All type 1 (AT1) receptor antagonist, candesartan cilexetil, and a vasodilator, hydralazine, were also examined. Results: Semiquantitative immunohistochemical evaluation and Western blot analysis showed that All significantly enhanced glomerular expression of SMemb (0.87 +/- 0.33 vs. 0.40 +/- 0.19 for immunohistochemical grading, p &lt; 0.05; 2.55 +/- 0.88 vs. 1.16 +/- 0.75 for Western blot analysis, p &lt; 0.05). Glomerular fibronectin was also increased in All-administered rats (301.7 &PLUSMN; 206.8 ng/5 pg protein vs. 95.8 &PLUSMN; 81.3 ng/5 pg protein, p &lt; 0.05). Candesartan cilexetil attenuated these effects. On the other hand, hydralazine did not change the glomerular expression of SMemb enhanced by All administration. Conclusion: All induced a phenotypic alteration in mesangial cells, enhanced the mesangial expression of SMemb and stimulated the fibronectin synthesis. These results suggest that the mesangial expression of SMemb is related to glomerular matrix accumulation and that All mediates both mesangial processes via AT1 receptors. Copyright (C) 2002 S. Karger AG, Basel.

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.

Na/Ca交換体(NCX)は,心筋細胞内からのCa2+汲み出しに中心的役割を果たす膜上タンパクであるが,その機能異常がどのような影響を生体に及ぼすのかは判っていない.今回我々は,NCXノックアウトヘテロ接合体(NCX KO)マウスと正常な同胞(WT)を用いてNCX機能異常に関する検討を行った.単離心室筋細胞を電気刺激し,細胞内Ca2+濃度([Ca2+]i)変化を観察した(fluo-3,室温).誘発された[Ca2+]iトランジェントの振幅はNCX KOで有意に大きく,続いてcaffeine(20mM)処理をして測定した筋小胞体(SR)内Ca2+量は,NCX KOで著明に増加していた.ノーザンブロットによるL型Ca2+チャネルの発現レベルに差がないことから,電気刺激時の[Ca+]i振幅の上昇はSR内Ca2+量の増加によるCa2+依存性Ca+放出の増強によるためと考えられた.これらの結果から,NCX KOマウス心室筋細胞はCa2+-overloadに陥りやすいと考えられた.横行大動脈部分に縮窄を形成し心肥大を誘発したところ,NCX KO心においてより顕著な肥大が観察された.心内圧測定の結果から,心内圧上昇がNCX KOマウスにおいてより大きかったことがその原因と推察された.血行動態上の拡張期dip&plateauパターンやドップラーエコー上の左室拡張早期流入血流減速時間(DCT)の短縮といった拡張不全所見を認めるなど,NCX KOにて心肥大が著明であることを示唆する生理学的所見も得られた.一方, WTではすでに収縮不全(EF低下)を呈しSR CaATPase(SERCA)の発現の低下も伴っていることから,心不全へ移行しているものと思われた.総括すると,NCX機能の低下は,圧負荷に対する肥大反応は加速するものの心不全への移行に関しては抑制的に作用すると考えられる.不全心ではNCXの発現および機能が上昇しているとされているが,このことからも心不全の進行にNCX機能変化が大きく関与する可能性が示唆された.

The aim of this study was to test the hypothesis that a subendocardial arrhythmogenic focus makes the heart more susceptible to VF due to electrical interaction with the Purkinje network. Monofocal ventricular tachycardia (mVT) was created by injecting 5-μg aconitine into the left ventricular subepicardium (EPI-mVT, n = 8) or subendocardium (ENDO-mVT, n = 13) in anesthetized dogs. Despite the similar cycle length of mVT, the incidence of VF was significantly different between EPI-mVT and ENDO-mVT (100 [8/8] vs 46% [6/13], P &lt 0.05). VF was invariably preceded by hemodynamic deterioration. Three-dimensional cardiac mapping (n = 10, 221 ± 11 recording sites) revealed that VF was triggered solely by focal firing unrelated to the primary arrhythmogenic focus in both mVT models. No interaction between the primary focus and adjacent endocardial tissue was indicated. These results suggest that the proximity of the arrhythmogenic focus to the Purkinje network has little role in cardiac vulnerability to VF, and that progression of mVT to VF is largely caused by sporadic focal firing regardless of the site of the arrhythmogenic focus in the present animal model.

Accelerated coronary arteriosclerosis remains a major problem for the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood and there is no effective therapy. Tranilast is a promising drug that may prevent postangioplasty restenosis. Here, we investigated whether orally administered tranilast inhibits the development of intima hyperplasia in a mouse model of cardiac transplantation. Cardiac allografts from BALB/c mice were transplanted heterotopically into C3H/He mice. Mice were administered either vehicle or tranilast everyday by gavage. Morphometrical analysis of the cardiac allografts harvested at 2 months revealed that the administration of tranilast significantly reduced the development of coronary atherosclerosis. In the mice treated with tranilast, upregulation of the cyclin-dependent kinase inhibitor p21 was observed in the allografts, accompanied by a reduced number of proliferating cells. Tranilast also suppressed transforming growth factor-beta (TGF-beta) expression. Tranilast may be effective in preventing transplant-associated arteriosclerosis through its anti-inflammatory and anti-proliferative effects. (C) 2001 Elsevier Science B.V All rights reserved.

BACKGROUND: We recently suggested that a rat aortotomy model could be substituted for a vascular anastomotic stricture around a suture line. The aim of this study was to verify such a rat aortotomy model using proliferating cell nuclear antigen (PCNA) immunohistochemistry, which is a sensitive method for detection of proliferating cells in vascular tissue after injury. METHODS: Longitudinal aortotomy was performed in the abdominal aorta of the rat subjects. The rats were sacrificed at 1, 2, 4 and 8 weeks following aortotomy (n=20 in each group). The control rats were sacrificed without aortotomy (n=20). The percentage of the lumen occluded by intimal thickening (I/M ratio) was calculated. All tissues were stained with antibodies against proliferating cell nuclear antigen (PCNA). RESULTS: Values of I/M ratio were 8.5+/-4.4%, 15.6+/-9.5%, 11.8+/-5.5%, 9.6+/-6.2% at 1, 2, 4, 8 weeks following aortotomy in the injured groups and 0.4+/-0.1% in the controls, respectively. Those values in the injured group increased significantly as compared to the controls. There were also significant differences between one week and two weeks following aortotomy. The PCNA labeling index at one week following aortotomy (21.4+/-2.7%) was significantly higher than at two weeks following aortotomy (2.8+/-1.9%). SMCs in the intima at four and eight weeks following aortotomy were completely negative for PCNA. CONCLUSIONS: The experimental rat aortotomy model was determined to be useful in the investigation of intimal thickening around the suture line.

Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARgamma and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARgamma by PPARgamma agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARgamma activity by heterozygous PPARgamma deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARgamma deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARgamma deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor alpha, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.

To elucidate pathophysiological roles of heme oxygenase (HO)-1 in regulation of vascular tone in vivo, we have developed and characterized transgenic (Tg) mice that overexpress HO-1 site specifically in vascular smooth muscle cells (VSMCs). The Tg mice were generated by use of human HO-1 cDNA under the control of SM22-alpha promoter. The HO-1 gene overexpression was demonstrated by Northern blot analysis and coincided with increases in the protein expression in VSMCs and total HO activities. Tg mice exhibited a significant increase in arterial pressure at various ages and displayed impaired nitrovasodilatory responses in isolated aortic segments versus nontransgenic littermates while enhancing their nitric oxide (NO) production. The pressure of Tg mice was unchanged by systemic administration of either N(omega)-nitro-L-arginine or SNP. Furthermore, the isolated aorta in these mice exhibited lesser extents of NO-elicited cGMP elevation via soluble guanylate cyclase (sGC), while exhibiting no notable downregulation of sGC expression. Such impairment of the NO-elicited cGMP increase was restored significantly by tin protoporphyrin IX, an HO inhibitor. On the other hand, 3-(5'-hydroxymethyl-2' furyl)-1-benzyl-indazol (YC-1), an NO-independent activator of sGC, increased cGMP and relaxed aortas from Tg mice to levels comparable with those from nontransgenic mice, which indicates that contents of functionally intact sGC are unlikely to differ between the two systems. These findings suggest that site-specific overexpression of HO-1 in VSMCs suppresses vasodilatory response to NO and thereby leads to an elevation of arterial pressure.

Recently, troglitazone has emerged as an insulin sensitizer for the treatment of type II diabetes. However, its effect on skeletal muscle glucose use (SMGU) has not been studied. Methods: To investigate the effect of troglitazone on SMGU in patients with type II diabetes, we undertook skeletal muscle F-18-FDG PET dynamic imaging under insulin clamping before and after administration of SMGU to 20 patients with type Ii diabetes. Data were compared with those for 12 age-matched healthy volunteers. Results: The whole-body glucose disposal rate (GDR) was significantly lower in patients 129.9 +/- 9.83 mu mol/min/kg) than in control subjects (55.6 +/- 16.5 mu mol/min/kg, P &lt; 0.01), as was the SMGU (patients, 3.27 +/-: 2.17 mu mol/min/kg; control subjects, 10.9 +/- 6.4 mu mol/min/kg; P &lt; 0.01). After the therapy, GDR significantly improved in patients (29.3 +/- 14.6 mu mol/min/kg, P &lt; 0.05), as did SMGU (5.96 +/- 2.11 mu mol/min/kg, P &lt; 0.05). When results for patients with and without hypertension were separately analyzed, a significant improvement in SMGU after troglitazone was seen in both normotensive and hypertensive patients 9 normotensive [n = 10]: baseline, 3.67 +/- 2.89 mu mol/min/kg; after therapy, 5.28 +/- 2.57 mu mol/min/kg; P &lt; 0.05; hypertensive [n = 10]: baseline, 2.89 +/- 1.22 mu mol/min/kg; after therapy, 4.72 +/- 1.39 mu mol/min/kg; P &lt; 0.05). GDR in patients with and without hypertension was significantly improved by troglitazone (normotensive: baseline, 17.9 +/- 10.2 mu mol/min/kg; after therapy, 31.9 +/- 15.9 mu mol/min/kg; P &lt; 0.01; hypertensive: baseline, 39.6 +/- 15.1 mu mol/min/kg; after therapy, 47.7 +/- 23.8 mu mol/min/kg; P &lt; 0.05). The plasma free fatty acid concentration during insulin clamping was not changed by troglitazone (baseline, 1.1 +/- 0.86 mEq/L; after therapy, 0.93 +/- 0.65 mEq/L; P = not significant). Conclusion: Troglitazone can improve whole-body insulin resistance through the improvement of SMGU but not through a decline in plasma free fatty acid concentration in patients with type II diabetes with or without hypertension.

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.

To determine the presence and functional role of the histamine H2 receptor (H2R) palmitoylation, a receptor with a Cys(305) to Ala (A(305) receptor) mutation was generated. Wild-type (WT) and A(305) receptors were tagged at their N-termini with a hemagglutinin (HA) epitope. WT, but not A(305). receptors incorporated [H-3]palmitate by metabolic labeling, indicating that the H2R is palmitoylated at Cys(305). Immunocytochemistry of WT and A(305) receptors expressed in COS7 cells revealed WT receptors to be distributed at the plasma membrane, while the majority of A(305) receptors were localized intracellularly with only a small portion being at the plasma membrane. However, the affinity of the A(305) receptor for tiotidine was comparable to that of the WT receptor. In addition. when the amounts of cell surface receptors as determined by anti-HA antibody binding were equivalent, A(305) receptors mediated production of more cAMP than WT receptors. Preincubation of COS7 cells expressing each receptor with 10(-5) M histamine for 30 min reduced subsequent cAMP production in response to histamine via the receptors to similar extents, indicating that palmitoylation is not necessary for desensitization. In addition, cell surface A(305) receptors were capable of being internalized from the cell surface at a rate and extent similar to those of WT receptors. Finally, CHO cell lines stably expressing either WT or A(305) receptors were incubated with 10(-5) M histamine for 1, 6, 12 and 24 h. Total amounts of WT and A305 receptors, as determined by tiotidine binding, were reduced by incubation, indicating downregulation. Downregulation of the A(305) receptor was more extensive than that of the WT receptor. Thus, palmitoylation of the H2R might be important for targeting to the cell surface and stability. (C) 2001 Elsevier Science B.V. All rights reserved.

BACKGROUND: It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet. METHODS AND RESULTS: In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg every second day) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg every second day but not with 0.01 mg/kg every second day of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment. CONCLUSIONS: These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

We studied whether plasma BNP concentration measurement was useful in screening for silent ischemia or asymptomatic cardiac dysfunctions in diabetic outpatients in daily clinical practice. Plasma BNP and ANP concentrations in 573 outpatients with diabetes were measured. Plasma BNP concentrations increased with complications of hypertension, heart diseases, cardiac dysfunction, diabetic neuropathy, diabetic nephopathy, and diabetic retinopathy. Plasma BNP also was significantly correlated with NYHA classification, blood pressure, cardio-thoracic-ratio (CTR), SV1 + SV5, 6, interventricular septum thickness, posterior wall thickness, left ventricular mass, and left ventricular mass index. In subjects without heart disease, plasma ANP concentrations showed a correlation with blood glucose, but plasma BNP concentrations did not show such a correlation. Receiver operating characteristic analysis revealed that plasma BNP concentrations showed sensitivity of 62.7% and specificity of 75.0% in detecting heart diseases or cardiac dysfunction. In addition, the result of logistic regression analysis indicated that plasma BNP measurement was the best clinical parameter in the prediction of heart diseases and cardiac dysfunction. Measurement of the plasma BNP concentrations is thus useful in diagnosing heart diseases in diabetic subjects in daily clinical practice. © 2001, THE JAPAN DIABETES SOCIETY. All rights reserved.

We report a case of intravascular lymphoma (IVL) complicated with Pneumocystis carinii pneumonia (PCP). A 65-year-old male complaining of dyspnea and dementia was diagnosed to have pulmonary IVL by transbronchial lung biopsy. Concomitantly, deoxyribonucleic acid sequence specific to Pneumocystis carinii was detected in bronchoalveolar lavage fluid by polymerase chain reaction. Differential responses to the sequential treatments for PCP and IVL implied that increased serum lactate dehydrogenase (LDH) was due to PCP, whereas hypoxemia and dementia were due to IVL. Although pulmonary IVL and PCP share many clinical presentations, exact diagnosis is essential for their successful treatment.

Previous studies with peritoneal macrophages obtained from macrophage scavenger receptor class A (MSR-A) knock-out mice showed that the endocytic uptake of advanced glycation end products (AGE) by macrophages was mediated mainly by MSR-A. However, it is controversial whether the endocytic uptake of intravenously injected AGE proteins by liver sinusoidal endothelial cells (LECs) is similarly explained by receptor-mediated endocytosis via MSR-A, The present study was conducted to compare the capacity to endocytose AGE proteins in LECs and peritoneal macrophages obtained from MSR-A knockout and littermate wild-type mice. The endocytic degradation capacity of MSR-A knock-out LECs for AGE-BSA was indistinguishable from that of wild-type LECs, whereas that of MSR-A knock-out peritoneal macrophages for AGE-BSA was decreased to 30% of that in wild-type cells. Similarly, the endocytic degradation of MSR-A knock-out LECs for acetylated low-density lipoprotein (acetyl-LDL) did not differ from that of wild-type LECs, whereas the endocytic degradation of acetyl-LDL by MSR-A knock-out peritoneal macrophages was less than 20% of that in wild-type cells. Furthermore, formalde-hydetreated serum albumin (f-Alb), a ligand known to undergo scavenger-receptor-mediated endocytosis by LECs, was effectively taken up by MSR-A knock-out LECs at a capacity that did not differ from that of wild-type LECs. Moreover, the endocytic uptake of AGE-BSA by LECs was effectively competed for by unlabelled f-Alb or acetyl-LDL. These results indicate that the scavenger-receptor ligands AGE proteins, acetyl-LDL and f-Alb are endocytosed by LECs through a non-MSR-A pathway.

OBJECTIVES: This study evaluated whether dobutamine gated blood pool scintigraphy can predict improvement of cardiac sympathetic nerve activity and cardiac function. METHODS: Sixteen patients(10 men and 6 women, mean age 59 +/- 13 years) with dilated cardiomyopathy underwent dobutamine gated blood pool scintigraphy to measure left ventricular ejection fraction (LVEF) using tracer at 0, 5, 10 and 15 micrograms/kg/min before treatment. Patients were divided into good responders (LVEF increase > or = 15%) 8 patients(GR Group) and poor responders(LVEF increase < 15%) 8 patients (PR Group) after treatment with beta-blocker or amiodarone with a background treatment of digitalis, diuretics and angiotensin converting enzyme inhibitor. I-123 metaiodobenzylguanidine(MIBG) imaging to evaluate cardiac sympathetic nerve activity and echocardiography were performed before and at one year after treatment. MIBG imaging was obtained 4 hours after tracer injection, and the heart/mediastinum count ratio(H/M ratio) calculated from the anterior planar image and the total defect score(TDS) from the single photon emission computed tomography image. LVEF and left ventricular endo-diastolic dimension (LVDd) were measured by echocardiography and New York Heart Association(NYHA) functional class was evaluated. RESULTS: The GR Group showed TDS decreased from 28 +/- 6 to 17 +/- 12(p < 0.05), H/M ratio increased from 1.79 +/- 0.26 to 2.07 +/- 0.32(p < 0.05), LVEF increased from 29 +/- 8% to 48 +/- 10%(p < 0.01), and LVDd decreased from 65 +/- 4 mm to 58 +/- 5 mm(p < 0.05). In contrast, the PR Group showed no significant changes in TDS, H/M ratio, LVEF and LVDd. NYHA functional class improved in both groups. The improvement was better in the GR Group than in the PR Group. CONCLUSIONS: Dobutamine gated blood pool scintigraphy is useful to predict the improvement of the cardiac sympathetic nerve activity and cardiac function, and symptoms after treatment in patients with dilated cardiomyopathy.

加齢マウスではトランスジェニックマウスにおいて腎障害の発症が特徴的であった.これは血圧上昇を伴わない程度のET-1過剰発現でも,長期間にわたると組織障害を生じることを示しており,ET-1トランスジェニックマウスは加齢に伴う臓器障害の病態モデルになることが期待される

急性心筋梗塞の診断には,病歴,理学所見,生理機能検査,画像,そして血液生化学的検査を用いて多角的に検討することが重要である.近年の研究の発展によって,日常検査で簡単かつ正確な診断ができる生化学検査が確立されてきた.急性心筋梗塞に対する血清診断は,心筋壊死の有無と壊死量の推定が主要な目的である.心筋壊死を迅速に,より特異的に捉えるマーカーが必要とされる.現在までに確立されてきた多くのマーカーの特徴をよく理解し,目的に応じて使い分けることにより,より正確な病態把握が可能になる.

血管平滑筋細胞は動脈硬化巣や血管再建術後の血管で増殖する。増殖刺激に反応して,平滑筋は収縮型から合成型形質へ変換する.血管平滑筋細胞の形質変換の分子機構の解明は,動脈硬化の成因に基づく新しい治療法の開発に結びつく可能性がある.<BR>胎児型平滑筋ミオシンSMembは平滑筋の脱分化に伴って著明に誘導される.SMemb遺伝子の上流-100bp付近にはGCに富むシスエレメントSE 1が存在する.我々は,サウスウエスタン法によってSMembのSE 1に結合する蛋白として,ホメオドメインを持つ蛋白HexとZn-finger構造を持つKruppel型転写因子BTEB 2のcDNAを単離した.<BR>BTEB 2は大動脈では胎児期に多く発現し,発生に伴って減少する.しかし,傷害動脈の新生内膜で増殖する平滑筋細胞に再発現する.また,BTEB 2は単に胎児型ミオシン重鎖遺伝子の発現を亢進させるだけでなく,組織因子,PDGF,iNOS遺伝子のプロモータも活性化する.さらに,BTEB 2遺伝子のロモータも活性化する.さらに,BTEB 2遺伝子のやEgr-1により誘導される.すなわち,増殖刺激と,血管病変に特有の平滑筋形質変換の間に介在する転写因子であると推測された.

症例は20歳女性. 新生児期より哺乳力弱く筋緊張低下を認め, その後, 肥満, 知能発育遅延, 原発性無月経を認めた. 1996年に尿糖を指摘され, 同年8月肥満精査, 糖尿病治療目的にて当科に入院した. BMI 50.8kg/m²と著明な肥満を認めた. 染色体検査の結果, Prader-Willi症候群 (PWS) と診断した, 頭部MRIにて脳梁の欠損が認められた. 本症例はPWSに脳梁欠損が合併した初めての報告と考えられる. また, FPG 180mg/dl, HbA1c 11.6%, 空腹時IRI 22.8μU/mlと高血糖, 高インスリン血症を認めた. 食事療法を行い, 体重91kgまで減少し血糖値も改善したため退院となった. しかし, 退院後に体重が増加し血糖コントロールが悪化したため, トログリタゾンの投与を開始した. 体重の増加を認めない期間はHbA₁cは順調に低下したが, 体重が増加するのに伴いHbA₁cは再び上昇した. 食事指導を繰り返しながらトログリタゾンを増量したところ, 体重は減少し血糖コントロールも改善した. 本症例より, トログリタゾンの血糖降下作用を継続させるためには食事指導の徹底による体重コントロールが大変重要であると考えられた.

Epidermal nevus syndrome is an unusual neurocutaneous disorder in which epidermal nevi are associated with abnormalities of the skeleton and central nervous system, including the eyes and somtimes the cardiovascular system. We treated a patient in whom the latter included renal artery stenosis. An 18-year-old man with epidermal nevi was diagnosed as having the syndrome based on the additional presence of scoliosis, an arachnoid cyst in the middle cranial fossa, and microphthalmos. Hypertension was diagnosed when the patient was 15 years old. The plasma renin activity (9.7 ng/ml/h) was elevated. Right renal artery stenosis was demonstrated by angiography, and the abdominal aorta was narrowed distal to the ostium of the superior mesenteric artery. The plasma renin activity in the right renal vein (16 ng/ml/h) was higher than contralaterally (10 ng/ml/h). Several cardiovascular manifestations have been reported as a complication of epidermal nevus syndrome. Hypertension in an individual with epidermal nevi and congenital anomalies should prompt a search for a vascular anomaly.