基本情報
研究キーワード
4研究分野
1委員歴
5-
2012年 - 2014年
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2014年
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2014年
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2014年
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2012年
受賞
7-
2010年3月
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2009年5月
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2006年11月
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2002年7月
論文
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IJC Heart & Vasculature 54 101507-101507 2024年10月
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Hypertension research : official journal of the Japanese Society of Hypertension 2024年9月19日The Japanese Society of Hypertension have established a blood pressure (BP) target of 130/80 mmHg for patients with coronary artery disease (CAD). We evaluated the data of 8793 CAD patients in the Clinical Deep Data Accumulation System database who underwent cardiac catheterization at six university hospitals and the National Cerebral and Cardiovascular Center (average age 70 ± 11 years, 78% male, 43% with acute coronary syndrome [ACS]). Patients were divided into two groups based on whether or not they achieved the guideline-recommended BP of <130/80 mmHg. We analyzed the relationship between BP classification and major adverse cardiac and cerebral event (MACCE) separately in two groups: those with ACS and those with chronic coronary syndrome (CCS). During an average follow-up period of 33 months, 710 MACCEs occurred. A BP below 130/80 mmHg was associated with fewer MACCEs in both the overall (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-1.00, p = 0.048) and the ACS group (HR 0.67, 95%CI 0.51-0.88, p = 0.003). In particular, stroke events were also lower among those with a BP below 130/80 mmHg in both the overall (HR 0.69, 95%CI 0.53-0.90, p = 0.006) and ACS groups (HR 0.44, 95%CI 0.30-0.67, p < 0.001). In conclusion, the achievement of BP guidelines was associated with improved outcomes in CAD patients, particularly in reducing stroke risk among those with ACS.
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International Journal of Cardiology: Cardiovascular Risk and Prevention 22 2024年9月The authors regret that the original version of the article incorrectly stated the study period as “April 2014 to March 2020" in both the Abstract and the Methods section. The correct study period should have been “April 2013 to March 2019". The authors would like to apologise for any inconvenience caused.
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JACC: Advances 3(7) 2024年7月Background: The prognostic implications of persistent low-grade inflammation in patients with chronic coronary syndrome (CCS) are underexplored. The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the benefit of higher intensity pitavastatin in Japanese patients with CCS. Objectives: This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic effect of the persistent low-grade inflammation represented by high-sensitivity C-reactive protein (hs-CRP) in CCS patients. Methods: The present analysis involved patients without events until 6 months after randomization and whose hs-CRP levels were available at baseline and 6 months (n = 10,460). The primary endpoint was the composite of cardiovascular mortality, myocardial infarction, stroke, and unstable angina hospitalization. Landmark analyses evaluated the prognostic impact of continuous inflammation in 4 groups based on the median levels of hs-CRP (0.5 mg/L for both) at baseline and 6 months. The 4 groups included patient with persistently low, elevated (increased), reduced, and persistently high hs-CRP. Results: Adjusted Cox proportional hazard analyses demonstrated an increased risk of the primary endpoint in the group with persistently high hs-CRP when compared to the group with persistently low hs-CRP as a reference (adjusted HR: 1.48, 95% CI: 1.18-1.89; P = 0.001), but with a similar risk in the group with elevated (HR: 1.07, 95% CI: 0.77-1.49, P = 0.68) and reduced (HR: 0.92; 95% CI: 0.66-1.27; P = 0.60) hs-CRP. Conclusions: The study shows that persistent low-grade inflammation is associated with poor outcomes and underscores the need to address residual inflammatory risk in CCS patients. (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease [REAL-CAD]; NCT01042730)
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JACC. Advances 3(7) 100996-100996 2024年7月BACKGROUND: The prognostic implications of persistent low-grade inflammation in patients with chronic coronary syndrome (CCS) are underexplored. The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the benefit of higher intensity pitavastatin in Japanese patients with CCS. OBJECTIVES: This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic effect of the persistent low-grade inflammation represented by high-sensitivity C-reactive protein (hs-CRP) in CCS patients. METHODS: The present analysis involved patients without events until 6 months after randomization and whose hs-CRP levels were available at baseline and 6 months (n = 10,460). The primary endpoint was the composite of cardiovascular mortality, myocardial infarction, stroke, and unstable angina hospitalization. Landmark analyses evaluated the prognostic impact of continuous inflammation in 4 groups based on the median levels of hs-CRP (0.5 mg/L for both) at baseline and 6 months. The 4 groups included patient with persistently low, elevated (increased), reduced, and persistently high hs-CRP. RESULTS: Adjusted Cox proportional hazard analyses demonstrated an increased risk of the primary endpoint in the group with persistently high hs-CRP when compared to the group with persistently low hs-CRP as a reference (adjusted HR: 1.48, 95% CI: 1.18-1.89; P = 0.001), but with a similar risk in the group with elevated (HR: 1.07, 95% CI: 0.77-1.49, P = 0.68) and reduced (HR: 0.92; 95% CI: 0.66-1.27; P = 0.60) hs-CRP. CONCLUSIONS: The study shows that persistent low-grade inflammation is associated with poor outcomes and underscores the need to address residual inflammatory risk in CCS patients. (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease [REAL-CAD]; NCT01042730).
MISC
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Circulation journal : official journal of the Japanese Circulation Society 67 380-380 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 333-333 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 323-323 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 195-195 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 213-213 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 195-195 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 198-198 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 210-210 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 192-192 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 268-268 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 265-265 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 153-153 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 147-147 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 151-151 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 143-144 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 140-140 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 139-140 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 153-153 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 307-307 2003年3月1日
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Circulation journal : official journal of the Japanese Circulation Society 67 358-358 2003年3月1日
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Hypertension research : official journal of the Japanese Society of Hypertension 26 Suppl S79-84-S84 2003年2月 査読有りAdrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.
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ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 23(2) 295-301 2003年2月Objective-We examined the possible association between insulin resistance and carotid arteriosclerosis in subjects who had both normal fasting glucose and normal glucose tolerance after intake of a glucose load. Methods and Results-Our subjects were individuals who underwent general health screening at our institute, which included carotid ultrasound and oral glucose tolerance testing. Of the 1238 subjects enrolled in our study, 738 (60%) were classified as normal, defined as a normal fasting glucose level and normal glucose tolerance, and 334 (27%) and 166 (13%) were classified as borderline and diabetic, respectively, according to the criteria of the Japan Diabetes Society. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to measure insulin resistance. In normal-type subjects, univariate analysis showed that insulin resistance, but not insulin secretion, was associated with the presence of carotid plaque. Multivariate analysis showed that HOMA-IR was positively associated with carotid plaque in normal-type subjects, with an odds ratio of 1.19 (95% confidence interval, 1.00 to 1.41; P<0.05). Conclusions-These data suggest the possibility that the presence of higher insulin resistance could be a risk factor for carotid arteriosclerosis in subjects with normal fasting glucose and normal glucose tolerance.
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The Journal of biological chemistry 278(4) 2461-8 2003年1月24日 査読有りThe adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and beta-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor alpha. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo. In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.
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炎症・再生 : 日本炎症・再生医学会雑誌 = Inflammation and regeneration 23(1) 44-50 2003年1月10日Exuberant accumulation of smooth muscle cells plays a principal role in the pathogenesis of vascular diseases. It has been assumed that smooth muscle cells derived from the adjacent medial layer migrate, proliferate and synthesize extracellular matrix. Although a lot of effort has been devoted targeting migration and proliferation of medial smooth muscle cells, no effective therapy to prevent occlusive vascular remodeling has been established. Here, we show that bone marrow cells give rise to the majority of smooth muscle cells that contribute to arterial remodeling in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis. Notably, purified hematopoietic stem cells differentiated into smooth muscle cells <I>in vitro</I> and <I>in vivo</I>. Our findings suggest that somatic stem cells contribute to pathological remodeling of remote organs. Our study provides the basis for the development of a new therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of bone marrow-derived vascular progenitor cells.
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Nippon rinsho. Japanese journal of clinical medicine 61(5) 857-861 2003年Diastolic dysfunction is now recognized as an important mechanism of heart failure, but treatment for diastolic failure has not yet been established. Many of causes for diastolic dysfunction have been related to myocardial hypertrophy or fibrosis. Until recently, angiotensin II has been proposed as one of important growth factors that lead into hypertrophy and fibrosis. Angiotensin II blockade, therefore, is a promising candidate for the treatment of diastolic failure. Two randomized studies with angiotensin II type 1 receptor blocker are under way. This review will describe the pathophysiologic basis for diastolic dysfunction, and discuss the possible treatments for diastolic failure referring to the recently-proposed two guidelines.
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Nippon rinsho. Japanese journal of clinical medicine 61 418-424 2003年
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Nippon rinsho. Japanese journal of clinical medicine 61 775-780 2003年
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JOURNAL OF PHARMACOLOGICAL SCIENCES 91 61P-61P 2003年
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JOURNAL OF PHARMACOLOGICAL SCIENCES 91 45P-45P 2003年
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Cardiology 100(2) 80-5 2003年 査読有りAtherectomy specimens offer an opportunity to study the biology of coronary artery lesions. We cultured smooth muscle cells (SMCs) from specimens obtained from 24 patients with coronary restenosis after angioplasty to study the relationship between activity of SMCs (in vitro outgrowth) and the time course of restenosis. We also examined expression of a Kruppel-like zinc-finger transcription factor 5 (KLF; also known as BTEB2 and IKLF), which is markedly induced in activated SMCs, in the same specimens. SMC outgrowth was observed in 9 of 24 specimens (37.5%). Restenosis occurred sooner (p < 0.01) in patients whose specimens showed outgrowth compared to those whose specimens showed no outgrowth. Immunostaining for KLF5 was more common in specimens with outgrowth (89 vs. 20%, p < 0.01). These data suggest that the number of activated SMCs in lesions may determine in vitro outgrowth and also affect the time to restenosis.
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社会技術研究論文集 1:383-390 383-390 2003年ミッションプログラム医療安全研究グループにおいては, 日々の診療で膨大に発生する各種の診療情報から, 情報処理技術の適用により医学的知見を抽出し, その知識を国内で共有化する為の汎用的な手法について研究を行っている. 研究にあたっては, 倫理面に配慮された適切な情報収集・管理手法によって得られた実際の診療情報を, 医学と工学, それぞれの専門家が共同で体系化することにより, 臨床的に有用な知見を得るにいたっている. これらの医学的成果及びその普及手段としての技術的成果を併せて報告する.
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Japanese heart journal 44(1) 139-44 2003年1月 査読有りA 74 year-old Japanese woman, who had suffered from Lambert-Eaton myasthenic syndrome (LEMS), Sjoegren's syndrome, and discoid lupus erythematosus for 10 years and had been successfully controlled by 3,4-diaminopyridine and prednisolone, began to suffer from chest discomfort at night. Stress-induced myocardial ischemia in the left ventricular anterior septum was detected by thallium-201 scintigraphy. After diltiazem was prescribed, she began to feel systemic malaise and weakness in both thighs. She stopped taking diltiazem and the symptoms improved. Coronary angiography revealed 75% stenosis with calcification in the middle of the left anterior descending artery. After atherectomy with a lotablator and coronary stenting, diltiazem was prescribed. She felt malaise again, but continued taking diltiazem. After three months a follow-up coronary angiography showed no restenosis in the lesion and diltiazem was stopped. The weakness and malaise disappeared and her muscle strength recovered. LEMS is an autoimmune disorder of peripheral cholinergic transmission in which autoantibodies to the presynaptic P/Q-type voltage-gated calcium channels (VGCC) decrease the release of acetylcholine at the neuromuscular junction resulting in muscle weakness. P/Q-type VGCC regulates most of the neurotransmitter release and L-type VGCC regulates the remainder. L-type VGCC blockers are thought to have little effect on the neuromuscular junction. but they should be used very carefully. even in the remission stage of LEMS, because of preexisting neuromuscular blocking in transmission.
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Genes to cells : devoted to molecular & cellular mechanisms 8(1) 29-40 2003年1月 査読有りBACKGROUND: Cytoskeletal reorganization is important for a wide variety of insulin-mediated biological actions, including cell growth, migration and metabolism, but the intracellular signalling pathways leading to insulin-induced cytoskeletal reorganization have largely been unknown. We therefore investigated the involvement of Grb2/Ash-Ras and phosphatidylinositol (PI) 3-kinase in the insulin-induced morphological changes in fibroblasts over-expressing human insulin receptors (HIRcB cells). RESULTS: Insulin, as well as 12-O-tetradecanoylphorbol-13-acetate (TPA) and 8-bromo-cAMP, induced a unique morphological change associated with actin cytoskeletal reorganization characterized by the disruption of actin stress fibres and thicker actin bundle formation. Microinjection of an anti-Grb2/Ash antibody, but not control IgG, inhibited the insulin-induced actin reorganization, whereas the TPA- and 8-bromo-cAMP-induced morphological changes were not inhibited by microinjection of the anti-Grb2/Ash antibody. In addition, microinjection of dominant negative ras p21 protein, but not the heat-treated protein, inhibited insulin-induced cytoskeletal reorganization. Microinjection of activated p21ras protein resulted in very similar cytoskeletal reorganization with actin bundle formation in the cytoplasm. The PI3-kinase inhibitor wortmannin inhibited insulin-induced cytoskeletal reorganization, but not the TPA- nor 8-bromo-cAMP-induced reorganization. Interestingly, wortmannin also inhibited the activated p21ras-induced morphological change. CONCLUSIONS: We concluded that Grb2/Ash-Ras activation and probably Ras-associated PI3-kinase activation are involved in the insulin-induced morphological change.
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CIRCULATION JOURNAL 67(1) 83-90 2003年1月Beta-adrenergic stimulation and the resultant Ca2+ load both seem to be associated with progression of heart failure as well as hypertrophy. Because the alpha(1)-, beta(1),(2)-blocker, carvedilol, has been shown to be outstandingly beneficial in the treatment of heart failure, its direct effects on intracellular calcium ion concentration ([Ca2+](i)), including antagonism to isoproterenol, in ventricular myocytes were investigated and then comapred with a selective beta(1)-blocker, atenolol, and a non-selective beta(1),(2)-blocker, timolol. At 1-300 nmol/L, carvedilol decreased the amplitude of [Ca2+](i) by similar to20% independently of its concentration, which was a similar effect to timolol. All the beta-blockers at 10 nmol/L decreased the amount of cAMP, but atenolol had the least effect. Carvedilol in the mumol/L order further diminished the amplitude of [Ca2+](i) transients, and at 10 mumol/L increased the voltage threshold for pacing myocytes. These effects were not observed with timolol or atenolol. L-type Ca2+ currents (I-Ca) were decreased by carvedilol in the mumol/L order in a concentration dependent manner. As for the beta-antagonizing effect, the concentrations of carvedilol, timolol, and atenolol needed to prevent the effect of isoproterenol by 50% (IC50) were 1.32, 2.01, and 612 nmol/L, respectively. Furthermore, the antagonizing effect of carvedilol was dramatically sustained even after removal of the drug from the perfusate. Carvedilol exerts negative effects on [Ca2+](i), including inhibition of the intrinsic beta-activity, reduction Of I-Ca in the mumol/L order, and an increase in the threshold for pacing at greater than or equal to10 mumol/L. Data on the IC50 for the isoproterenol effect suggest that carvedilol could effectively inhibit the [Ca2+](i) load induced by catecholamines under clinical conditions.
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CIRCULATION JOURNAL 67(1) 26-30 2003年1月A link between certain infectious microorganisms and an increased risk of atherosclerotic disease has been suggested. By analyzing the data of subjects who had undergone general health-screening tests, a possible association between carotid atherosclerosis and seropositivity of antibody against hepatitis C virus (HCV) has been previously reported. In the present study, a possible link between carotid atherosclerosis and HCV core protein positivity was assessed, because it is postulated to be a better marker of viremia and thus persistent infection. Of the 1992 enrolled subjects, 496 (25%) had carotid artery plaque, and 25 (1.3%) were positive for HCV core protein. Carotid artery plaque was positive in 480/1967 (24%) and 16/25 (64%) of the core protein-negative and core protein-positive subjects, respectively (p<0.0001 by chi(2) test). Serum concentrations of transaminases were higher in core protein-positive subjects, but albumin concentrations were not significantly different between the 2 groups. Multivariate logistic regression analysis showed that HCV core protein positivity is an independent predictor of carotid plaque with an odds ratio of 5.61 (95% confidence interval 2.06-15.26, p<0.001). These data further support the possible link between persistent HCV infection and carotid atherosclerosis in the subjects without severe liver dysfunction.
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Journal of Japan Society of Computer Aided Surgery : J.JSCAS 4(3) 105-106 2002年12月30日
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Circulation research 91(12) 1103-13 2002年12月13日 査読有りStructural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling. This review addresses the functional role played by cardiac fibroblasts and the molecular mechanisms that govern their activity during cardiac hypertrophy and remodeling. A particular focus is the recent progress toward our understanding of the transcriptional regulatory mechanisms involved.
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Circulation 106(24) 3111-9 2002年12月10日 査読有りBACKGROUND: The effects of lysophosphatidylcholine (LPC) on electrophysiological activities and intracellular Ca2+ concentration ([Ca2+]i) were investigated in coronary arterial smooth muscle cells (CASMCs). METHODS AND RESULTS: The patch clamp techniques and Ca2+ measurements were applied to cultured rabbit CASMCs. The membrane potential was -46.0+/-5.0 mV, and LPC depolarized it. Replacement of extracellular Na+ with NMDG+ hyperpolarized the membrane and antagonized the depolarizing effects of LPC. In Na+-, K+-, or Cs+-containing solution, the voltage-independent background current with reversal potential (E(r)) of approximately +0 mV was observed. Removal of Cl- failed to affect it. When extracellular cations were replaced by NMDG+, E(r) was shifted to negative potentials. La3+ and Gd3+ abolished the background current, but nicardipine and verapamil did not inhibit it. In Na+-containing solution, LPC induced a voltage-independent current with E(r) of approximately +0 mV concentration-dependently. Similar current was recorded in K+- and Cs+-containing solution. La3+ and Gd3+ inhibited LPC-induced current, but nicardipine and verapamil did not inhibit it. In cell-attached configurations, single-channel activities with single-channel conductance of approximately 32pS were observed when patch pipettes were filled with LPC. LPC increased [Ca2+]i as the result of Ca2+ influx, and La3+ completely antagonized it. CONCLUSIONS: These results suggest that (1) nonselective cation current (I(NSC)) contributes to form membrane potentials of CASMCs and (2) LPC activates I(NSC), resulting in an increase of [Ca2+]i. Thus, LPC may affect CASMC tone under various pathophysiological conditions such as ischemia.
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CIRCULATION 106(19) 215-215 2002年11月
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CIRCULATION 106(19) 182-182 2002年11月
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CIRCULATION 106(19) 165-166 2002年11月
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CIRCULATION 106(19) 288-289 2002年11月
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CIRCULATION 106(19) 137-137 2002年11月
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Nature medicine 8(11) 1288-95 2002年11月 査読有りAdiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 298(4) 493-500 2002年11月A homeobox-containing transcription factor Csx/Nkx2-5 is an important regulator of cardiac development. Many different human CSX/NKX2-5 mutations have been reported to cause congenital heart disease. We here examined the effects of three representative CSX/NKX2-5 mutations on cardiomyocyte differentiation and death with the use of the P19CL6 cardiomyogenic cell. lines. Stable overexpression of wild-type CSX/NKX2-5 enhanced expression of cardiac-specific genes such as MEF2C and MLC2upsilon, the promoter activity of the atrial natriuretic peptide gene, and the terminal differentiation of P19CL6 into cardiomyocytes, while all CSX/NKX2-5 mutants attenuated them by different degrees. When exposed to H2O2 or cultured without change of the medium, many differentiated P19CL6 cells overexpressing the mutants, especially the mutant which lacks the carboxyl terminal region just after the homeodomain, were dead, while most of the cells overexpressing wild-type CSX/NKX2-5 survived. Overexpression of the carboxyl terminus-deleted mutant down-regulated expression of an anti-apoptotic protein Bcl-x(L) and up-regulated that of a proapoptotic protein CAS, while in the cells overexpressing wild-type CSX/NKX2-5, expression of a pro-apoptotic protein RIP was reduced. Furthermore, overexpression of wild-type CSX/NKX2-5 decreased the number of H2O2-induced TUNEL-positive cultured cardiomyocytes of neonatal rats, whereas overexpression of the mutants enhanced it. These results suggest that Csx/Nkx2-5 not only regulates expression of cardiac-specific genes but protects cardiomyocytes from stresses and that cell death may be another cause for the cardiac defects induced by human CSX/NKX2-5 mutations. (C) 2002 Elsevier Science (USA). All rights reserved.
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American journal of physiology. Lung cellular and molecular physiology 283(5) L963-70-L970 2002年11月 査読有りBronchial hyperresponsiveness and eosinophilia are major characteristics of asthma. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. In the present study, we questioned whether CGRP might have pathophysiological roles in airway hyperresponsiveness and eosinophilia in asthma. To determine the exact roles of endogenous CGRP in vivo, we chose to study antigen-induced airway responses using CGRP gene-disrupted mice. After ovalbumin sensitization and antigen challenge, we assessed airway responsiveness and measured proinflammatory mediators. In the sensitized CGRP gene-disrupted mice, antigen-induced bronchial hyperresponsiveness was significantly attenuated compared with the sensitized wild-type mice. Antigen challenge induced eosinophil infiltration in bronchoalveolar lavage fluid, whereas no differences were observed between the wild-type and CGRP-mutant mice. Antigen-induced increases in cysteinyl leukotriene production in the lung were significantly reduced in the CGRP-disrupted mice. These findings suggest that CGRP could be involved in the antigen-induced airway hyperresponsiveness, but not eosinophil infiltration, in mice. The CGRP-mutant mice may provide appropriate models to study molecular mechanisms underlying CGRP-related diseases.
書籍等出版物
21-
Springer 2009年 (ISBN: 9784431877745)
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Signal Transduction and Cardiac Hypertrophy (Naranjan S. Dhalla, Larry Hryshko, Elissavet Kardami, Pawan K. Singal, KLUWER ACADEMIC PUBLISHERS) 2003年
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Signal Transduction and Cardiac Hypertrophy (Naranjan S. Dhalla, Larry Hryshko, Elissavet Kardami, Pawan K. Singal, KLUWER ACADEMIC PUBLISHERS) 2003年
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Rapid Cycle Real-Time PCR : methods and applications 2001年
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in"The Hypertrophied Heart" 2000年
共同研究・競争的資金等の研究課題
91-
日本学術振興会 科学研究費助成事業 2023年4月 - 2026年3月
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日本学術振興会 科学研究費助成事業 2020年7月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2019年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2019年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2018年6月 - 2023年3月