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ABSTRACT: Chronotherapy has the potential to improve blood pressure (BP) variability and to decrease stroke and cardiovascular events. The present study examined the efficacy and safety of the bedtime administration in amlodipine-olmesartan combination therapy, as compared with the morning administration. The present study was an open-label, randomized crossover study of the effects of the morning vs. bedtime administration of amlodipine-olmesartan combination. The subject was 31 essential hypertensive patients. Morning BP surge (MBPS) and nocturnal BP pattern were analyzed from ambulatory BP data. Glucose and lipid profiles and cardiovascular-renal data were also collected. The bedtime administration reduced MBPS significantly (24.2 ± 13.5 mmHg vs. 32.3 ± 14.2 mmHg, p < 0.001) with no excessive nocturnal BP fall. In nondipper, the bedtime administration significantly improved nocturnal BP. On the other hand, it did not reduce nocturnal BP in dipper. Urinary albumin/creatinine ratio was lower in the bedtime administration than in the morning administration (42.5 ± 59.9 mg/g vs. 75.3 ± 26.4 mg/g, p = 0.044). In amlodipine-olmesartan combination therapy, the bedtime administration reduced better MBPS with correcting nocturnal BP fall and improved urinary albumin excretion. The bedtime dosing of amlodipine and olmesartan seems more apt than the morning dose to obtain the therapeutic goal.
Clinical and Experimental Hypertension 01/2010; 32(7):416-22. · 1.07 Impact Factor
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ABSTRACT: To identify novel transmembrane and secretory molecules expressed in cardiac myocytes, signal sequence trap screening was performed in rat neonatal cardiac myocytes. One of the molecules identified was a transmembrane protein, prostatic androgen repressed message-1 (PARM-1). While PARM-1 has been identified as a gene induced in prostate in response to castration, its function is largely unknown. Our expression analysis revealed that PARM-1 was specifically expressed in hearts and skeletal muscles, and in the heart, cardiac myocytes, but not non-myocytes expressed PARM-1. Immunofluorescent staining showed that PARM-1 was predominantly localized in endoplasmic reticulum (ER). In Dahl salt-sensitive rats, high-salt diet resulted in hypertension, cardiac hypertrophy and subsequent heart failure, and significantly stimulated PARM-1 expression in the hearts, with a concomitant increase in ER stress markers such as GRP78 and CHOP. In cultured cardiac myocytes, PARM-1 expression was stimulated by proinflammatory cytokines, but not by hypertrophic stimuli. A marked increase in PARM-1 expression was observed in response to ER stress inducers such as thapsigargin and tunicamycin, which also induced apoptotic cell death. Silencing PARM-1 expression by siRNAs enhanced apoptotic response in cardiac myocytes to ER stresses. PARM-1 silencing also repressed expression of PERK and ATF6, and augmented expression of CHOP without affecting IRE-1 expression and JNK and Caspase-12 activation. Thus, PARM-1 expression is induced by ER stress, which plays a protective role in cardiac myocytes through regulating PERK, ATF6 and CHOP expression. These results suggested that PARM-1 is a novel ER transmembrane molecule involved in cardiac remodeling in hypertensive heart disease.
PLoS ONE 01/2010; 5(3):e9746. · 4.09 Impact Factor
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Jun Shiraishi,
Yoshio Kohno,
Takahisa Sawada,
Mitsuo Takeda,
Masayasu Arihara,
Masayuki Hyogo,
Takatomo Shima,
Takashi Okada,
Takeshi Nakamura,
Satoaki Matoba,
Hiroyuki Yamada,
Akiyoshi Matsumuro,
Takeshi Shirayama,
Makoto Kitamura,
Keizo Furukawa, Hiroaki Matsubara
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ABSTRACT: Recurrent acute myocardial infarction (AMI) is a disastrous condition with high in-hospital morbidity and mortality. However, the relation between location of previous myocardial infarction (MI) and in-hospital outcome in repeat-AMI patients undergoing primary percutaneous coronary intervention (PCI) remains unclear.
Using the AMI-Kyoto Multi-Center Risk Study database, clinical background, angiographic findings, results of primary PCI, and in-hospital prognosis were retrospectively compared between primary PCI-treated AMI patients with previous anterior MI (anterior group, n=151) and those with previous non-anterior MI (non-anterior group, n=157). Clinical backgrounds, angiographic findings, results of primary PCI, and in-hospital outcome did not differ significantly between the two groups. On multivariate analysis, Killip class > or =3 at admission, number of diseased vessels > or =2 or diseased left main trunk at initial coronary angiography, and age were the independent predictors of in-hospital mortality in the recurrent-AMI patients, but not the anterior location of previous MI.
These results suggest that among recurrent-AMI patients undergoing primary PCI, in-hospital prognosis mostly depends on the severity of acute heart failure at the onset and the residual myocardial ischemia rather than previous MI sites.
Journal of Cardiology 01/2010; 55(1):77-83. · 1.28 Impact Factor
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Naohiko Nakanishi,
Takahisa Sawada,
Rena Sato,
Kenji Yanishi,
Yoshiki Akakabe,
Shinya Nishizawa,
Akira Kuroyanagi,
Yoshinori Tsubakimoto,
Akihiro Matsui,
Takeshi Nakamura,
Hirokazu Shiraishi,
Akiyoshi Matsumuro,
Takeshi Shirayama, Hiroaki Matsubara
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ABSTRACT: There are more than a few risks of hemorrhage complication in patients with amyloidosis. Although most cases with amyloidosis exhibit minor bleeding manifestations, they can be occasionally associated with life-threatening problems. To our knowledge, there are only a few cases of spontaneous pericardial hematoma associated with amyloidosis. We here report a patient who suddenly died of cardiac tamponade with massive pericardial hematoma 7 years after the diagnosis of familial amyloid polyneuropathy (FAP). A 69-year-old female with FAP with cardiogenic shock was admitted to our emergency room. Although she previously underwent permanent pacemaker implantation for atrial fibrillation with slow ventricular response, electrocardiogram showed a critical pacing failure. Emergent telemetry check revealed a sudden extreme increase of pacing capture threshold in the right ventricle. Maximum pacing voltage could not improve the critical condition, and she died 7 h after arrival. Autopsy showed a massive pericardial hematoma in the right ventricular free wall, and microscopic examination revealed typical amyloid deposition in the arterial wall of the pericardium. In this case, it is assumed that a sudden rupture of fragile pericardial vessels with amyloid deposition led to the lethal pericardial hematoma.
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 12/2009; 16(4):221-5. · 2.12 Impact Factor
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ABSTRACT: We describe a case of isolated adrenocorticotropic hormone deficiency that showed ventricular fibrillation associated with QT prolongation. A 72-year-old man was admitted because of consciousness disorder caused by severe hypoglycemia. On the second hospital day, QT intervals were unexpectedly prolonged and ventricular fibrillation occurred. Electrical defibrillation was performed and restored hemodynamically stable condition without neurologic deficits. He was diagnosed with endocrine tests as having isolated adrenocorticotropic hormone deficiency. QT prolongation was improved after hydrocortisone replacement therapy. We considered the QT prolongation was caused by corticosteroid insufficiency. We should be aware that corticosteroid insufficiency may provoke QT prolongation responsible for sudden cardiac death.
The American journal of emergency medicine 11/2009; 27(9):1167.e1-3. · 1.54 Impact Factor
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Shoken Honsho,
Susumu Nishikawa,
Katsuya Amano,
Kan Zen,
Yasushi Adachi,
Eigo Kishita,
Akihiro Matsui,
Asako Katsume,
Shinichiro Yamaguchi,
Kenichiro Nishikawa,
Kikuo Isoda,
David W H Riches,
Satoaki Matoba,
Mitsuhiko Okigaki, Hiroaki Matsubara
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ABSTRACT: It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1beta has also been shown to induce cardiomyocyte hypertrophy. Thus, the role of IL-1 in the heart remains to be determined.
We studied the role of hypertrophy signal-mediated IL-1beta/insulin-like growth factor (IGF)-1 production in regulating the progression from compensative pressure-mediated hypertrophy to heart failure.
Pressure overload was performed by aortic banding in IL-1beta-deficient mice. Primarily cultured cardiac fibroblasts (CFs) and cardiac myocytes (CMs) were exposed to cyclic stretch. Heart weight, myocyte size, and left ventricular ejection fraction were significantly lower in IL-1beta-deficient mice (20%, 23% and 27%, respectively) than in the wild type 30 days after aortic banding, whereas interstitial fibrosis was markedly augmented. DNA microarray analysis revealed that IGF-1 mRNA level was markedly (approximately 50%) decreased in the IL-1beta-deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1beta and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1beta-deficient CFs. IL-1beta released by stretch is at a low level unable to induce IL-6 but sufficient to stimulate IGF-1 production. Promoter analysis showed that stretch-mediated IL-1beta activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1beta deficiency markedly increased c-Jun N-terminal kinase (JNK) and caspase-3 activities and enhanced myocyte apoptosis and fibrosis, whereas replacement of IGF-1 or JNK inhibitor restored them.
We demonstrate for the first time that pressure-mediated hypertrophy and mechanical stretch generates a subinflammatory low level of IL-1beta, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis.
Circulation Research 10/2009; 105(11):1149-58. · 9.49 Impact Factor
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Hirokazu Yokoi,
Hiroyuki Yamada,
Yoshinori Tsubakimoto,
Hiroki Takata,
Hiroyuki Kawahito,
Sou Kishida,
Taku Kato,
Akihiro Matsui,
Hideyo Hirai,
Eishi Ashihara,
Taira Maekawa,
Masaru Iwai,
Masatsugu Horiuchi,
Kouji Ikeda,
Tomosaburo Takahashi,
Mitsuhiko Okigaki, Hiroaki Matsubara
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ABSTRACT: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) and vascular smooth muscle progenitor cells (VPCs) contribute to neointima formation, whereas the angiotensin II (Ang II) type 1 receptor (AT(1))-mediated action on BM-derived progenitors remains undefined.
A wire-induced vascular injury was performed in the femoral artery of BM-chimeric mice whose BM was repopulated with AT(1)-deficient (BM-Agtr1(-/-)) or wild-type (BM-Agtr1(+/+)) cells. Neointima formation was profoundly reduced by 38% in BM-Agtr1(-/-) mice. Although the number of circulating EPCs (Sca-1(+)Flk-1(+)) and extent of reendothelialization did not differ between the 2 groups, the numbers of both circulating VPCs (c-Kit(-)Sca-1(+)Lin(-)) and tissue VPCs (Sca-1(+)CD31(-)) incorporated into neointima were markedly decreased in BM-Agtr1(-/-) mice. The accumulation of aggregated platelets and their content of stromal cell-derived factor-1alpha (SDF-1alpha) were significantly reduced in BM-Agtr1(-/-) mice, accompanied by a decrease in the serum level of SDF-1alpha. Thrombin-induced platelets aggregation was dose-dependently inhibited (45% at 0.1 IU/mL, P<0.05) in Agtr1(-/-) platelets compared with Agtr1(+/+) platelets, accompanied by the reduced expression and release of SDF-1alpha.
The BM-AT(1) receptor promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs in a platelet-derived SDF-1alpha-dependent manner without affecting EPC-mediated reendothelialization.
Arteriosclerosis Thrombosis and Vascular Biology 10/2009; 30(1):60-7. · 6.37 Impact Factor
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Maki Uraoka,
Koji Ikeda,
Yusuke Nakagawa,
Masahiro Koide,
Yoshiki Akakabe,
Ritsuko Nakano-Kurimoto,
Tomosaburo Takahashi,
Satoaki Matoba,
Hiroyuki Yamada,
Mitsuhiko Okigaki, Hiroaki Matsubara
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ABSTRACT: Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion. MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.
Biochemical and Biophysical Research Communications 10/2009; 390(4):1202-7. · 2.48 Impact Factor
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ABSTRACT: A 64-year-old man complaining of resting angina underwent emergent coronary angiogram and significant stenosis in the mid-left anterior descending artery was discovered. Although deployment of the drug-eluting Cypher stent relieved the stenosis, the guiding catheter accidentally induced coronary dissection in the left main coronary artery (LMCA). Then, deployment of another Cypher stent at the lesion successfully managed the complication. 20 days later, although asymptomatic, extensive aortic dissection was detected from the coronary sinus of Valsalva to the femoral artery. 64-Row multidetector computed tomography demonstrated that the dissection originated from the LMCA and retrogradely expanded to the aorta. This type of dissection is a rare complication related to coronary intervention and even in such a clinical setting, asymptomatic delayed progression of retrograde aortic dissection has not previously been reported to our knowledge.
Journal of Cardiology 09/2009; 54(1):128-33. · 1.28 Impact Factor
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ABSTRACT: A 49-year-old woman presenting with leg edema and progressive dyspnea on exertion was found to have a diastolic murmur. Echocardiography revealed increased left ventricular volume and severe aortic regurgitation (AR). She also had pain in her chest and left shoulder. Gallium scintigraphy showed increased uptake in the sternum, and further examination indicated chronic osteomyelitis in the sternum and the proximal portion of bilateral clavicles. Aortic valve replacement was performed and the ascending aorta was found to have inflammatory wall thickening with adhesion formation. Histological study and other postoperative examinations revealed Takayasu's arteritis (TA). Involvement of bone is rarely described in TA, and typical manifestations such as claudication of extremities, decreased brachial artery pulse, and arteriogram abnormality were absent, which made the preoperative diagnosis difficult. Here we report a case of severe AR due to TA which presented much difficulty in the diagnosing process, because a rare complicated illness, osteomyelitis was clinically apparent and there were few clinical manifestations related to TA.
Journal of Cardiology 09/2009; 54(1):148-52. · 1.28 Impact Factor
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Seimi Satomi-Kobayashi,
Tomomi Ueyama,
Steffen Mueller,
Ryuji Toh,
Tomoya Masano,
Tsuyoshi Sakoda,
Yoshiyuki Rikitake,
Jun Miyoshi, Hiroaki Matsubara,
Hidemasa Oh,
Seinosuke Kawashima,
Ken-ichi Hirata,
Yoshimi Takai
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ABSTRACT: The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca(2+)-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload-induced cardiac dysfunction.
Hypertension 09/2009; 54(4):825-31. · 6.21 Impact Factor
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Ritsuko Nakano-Kurimoto,
Koji Ikeda,
Maki Uraoka,
Yusuke Nakagawa,
Kotaro Yutaka,
Masahiro Koide,
Tomosaburo Takahashi,
Satoaki Matoba,
Hiroyuki Yamada,
Mitsuhiko Okigaki, Hiroaki Matsubara
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ABSTRACT: Medial artery calcification, which does not accompany lipid or cholesterol deposit, preferentially occurs in elderly population, but its underlying mechanisms remain unclear. In the present study, we investigated the potential role of senescent vascular smooth muscle cells (VSMCs) in the formation of senescence-associated medial calcification. Replicative senescence was induced by the extended passages (until passages 11-13) in human primary VSMCs, and cells in early passage (passage 6) were used as control young cells. VSMC calcification was markedly enhanced in the senescent cells compared with that in the control young cells. We identified that genes highly expressed in osteoblasts, such as alkaline phosphatase (ALP) and type I collagen, were significantly upregulated in the senescent VSMCs, suggesting their osteoblastic transition during the senescence. Knockdown of either ALP or type I collagen significantly reduced the calcification in the senescent VSMCs. Of note, runt-related transcription factor-2 (RUNX-2), a core transcriptional factor that initiates the osteoblastic differentiation, was also upregulated in the senescent VSMCs. Knockdown of RUNX-2 significantly reduced the ALP expression and calcification in the senescent VSMCs, suggesting that RUNX-2 is involved in the senescence-mediated osteoblastic transition. Furthermore, immunohistochemistry of aorta from the klotho(-/-) aging mouse model demonstrated in vivo emergence of osteoblast-like cells expressing RUNX-2 exclusively in the calcified media. We also found that statin and Rho-kinase inhibitor effectively reduced the VSMC calcification by inhibiting P(i)-induced apoptosis and potentially enhancing matrix Gla protein expression in the senescent VSMCs. These findings strongly suggest an important role of senescent VSMCs in the pathophysiology of senescence-associated medial calcification, and the inhibition of osteoblastic transition could be a new therapeutic approach for the prevention of senescence-associated medial calcification.
AJP Heart and Circulatory Physiology 09/2009; 297(5):H1673-84. · 3.71 Impact Factor
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ABSTRACT: Erythropoietin (EPO) has been shown to have effects beyond hematopoiesis, such as prevention of cardiac apoptosis. The purpose of the current study is to examine the influence of the time-course change in the serum concentration of endogenous EPO on cardiac functions in the chronic phase in patients with acute coronary syndrome, who successfully achieved reperfusion by primary percutaneous coronary intervention (PCI).
The prospective study included 34 patients with angiographically documented coronary artery disease, including 24 patients with acute myocardial infarction (AMI) and 10 patients with unstable angina pectoris (UAP) who underwent successful PCI within 24 h from the onset. Serum EPO concentration significantly increased at Day 3 and Day 7 compared with that at Day 1 in the AMI group, and the level at Day 3 was significantly higher in the AMI group than in the UAP group. There were significant correlations between DeltaEPO and Delta left ventricular ejection fraction (LVEF) or Delta left ventricular end-diastolic volume index and between peak EPO concentration and DeltaLVEF.
These data showed the time-dependent increase of serum EPO in AMI patients after primary PCI, indicating its possible contribution to cardioprotective effect in the chronic phase.
Circulation Journal 09/2009; 73(10):1920-6. · 3.77 Impact Factor
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ABSTRACT: The objective was to assess the add-on effect of valsartan on top of the conventional treatment for high-risk hypertension in terms of the morbidity and mortality.
The KYOTO HEART Study was of a multicentre, Prospective Randomised Open Blinded Endpoint (PROBE) design, and the primary endpoint was a composite of fatal and non-fatal cardiovascular events (clintrials.gov NCT00149227). A total of 3031 Japanese patients (43% female, mean 66 years) with uncontrolled hypertension were randomized to either valsartan add-on or non-ARB treatment. Median follow-up period was 3.27 years. In both groups, blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study. Compared with non-ARB arm, valsartan add-on arm had fewer primary endpoints (83 vs. 155; HR 0.55, 95% CI 0.42-0.72, P = 0.00001).
Valsartan add-on treatment to improve blood pressure control prevented more cardiovascular events than conventional non-ARB treatment in high-risk hypertensive patients in Japan. These benefits cannot be entirely explained by a difference in blood pressure control.
European Heart Journal 09/2009; 30(20):2461-9. · 10.48 Impact Factor
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Yoshinori Tsubakimoto,
Hiroyuki Yamada,
Hirokazu Yokoi,
Sou Kishida,
Hiroki Takata,
Hiroyuki Kawahito,
Akihiro Matsui,
Norifumi Urao,
Yoshihisa Nozawa,
Hideyo Hirai,
Jiro Imanishi,
Eishi Ashihara,
Taira Maekawa,
Tomosaburo Takahashi,
Mitsuhiko Okigaki, Hiroaki Matsubara
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ABSTRACT: The angiotensin II (Ang II) type 1 (AT(1)) receptor is expressed in bone marrow (BM) cells, whereas it remains poorly defined how Ang II regulates differentiation/proliferation of monocyte-lineage cells to exert proatherogenic actions.
We generated BM chimeric apoE(-/-) mice repopulated with AT(1)-deficient (Agtr1(-/-)) or wild-type (Agtr1(+/+)) BM cells. The atherosclerotic development was significantly reduced in apoE(-/-)/BM-Agtr1(-/-) mice compared with apoE(-/-)/BM-Agtr1(+/+) mice, accompanied by decreased numbers of BM granulocyte/macrophage progenitors (GMP:c-Kit(+)Sca-1(-)Lin(-)CD34(+)CD16/32(+)) and peripheral blood monocytes. Macrophage-colony-stimulating factor (M-CSF)-induced differentiation from hematopoietic stem cells (HSCs:c-Kit(+)Sca-1(+)Lin(-)) to promonocytes (CD11b(high)Ly-6G(low)) was markedly reduced in HSCs from Agtr1(-/-) mice. The expression of M-CSF receptor c-Fms was decreased in HSCs/promonocytes from Agtr1(-/-) mice, accompanied by a marked inhibition in M-CSF-induced phosphorylation of PKC-delta and JAK2. c-Fms expression in HSCs/promonocytes was mainly regulated by TNF-alpha derived from BM CD45(-)CD34(-) stromal cells, and Ang II specifically regulated the TNF-alpha synthesis and release from BM stromal cells.
Ang II regulates the expression of c-Fms in HSCs and monocyte-lineage cells through BM stromal cell-derived TNF-alpha to promote M-CSF-induced differentiation/proliferation of monocyte-lineage cells and contributes to the proatherogenic action.
Arteriosclerosis Thrombosis and Vascular Biology 08/2009; 29(10):1529-36. · 6.37 Impact Factor
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Tetsuro Kusaba,
Yasukiyo Mori,
Okagaki Masami,
Neriya Hiroko,
Takaomi Adachi,
Chikako Sugishita,
Kazuhiro Sonomura,
Taikou Kimura,
Noriko Kishimoto,
Hisako Nakagawa,
Mitsuhiko Okigaki,
Tsuguru Hatta, Hiroaki Matsubara
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ABSTRACT: Sodium restriction is important in the treatment of chronic kidney disease; however, it is sometimes difficult to achieve. Decreased taste sensitivity may be a factor influencing inadequate control of oral salt intake and subsequent high blood pressure. To measure this, the gustatory threshold (recognition and detection) for salty taste was determined in 29 patients with chronic kidney disease using a sodium-impregnated test strip and relevant factors determining taste sensitivity were analyzed. Compared with 11 healthy volunteers, recognition and detection thresholds were increased in the patients with chronic kidney disease. Oral sodium intake correlated positively but serum zinc correlated negatively with the recognition threshold. Patients with diabetic nephropathy had a higher detection threshold than non-diabetic patients. Both recognition and detection thresholds were increased in patients with diuretic administration. After 1 week of sodium restriction, the average recognition threshold decreased significantly. Our study verified that latent taste dysfunction and zinc deficiency are common in patients with chronic kidney disease. Further, the recognition threshold for salty taste improved even after a short period of salt restriction.
Kidney International 07/2009; 76(6):638-43. · 6.61 Impact Factor
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Hideki Yamahara,
Noriko Kishimoto,
Midori Nakata,
Akiko Okazaki,
Taikou Kimura,
Kazuhiro Sonomura,
Eiko Matsuoka,
Yayoi Shiotsu,
Takaomi Adachi, Hiroaki Matsubara,
Toshiji Iwasaka,
Yasukiyo Mori
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ABSTRACT: Peritoneal fibrosis leads to discontinuation of peritoneal dialysis. Although aldosterone promotes tissue fibrosis in many organs, its contribution to peritoneal fibrosis and the underlying mechanism are poorly understood. The present study investigated the direct effect of aldosterone on cultured rat peritoneal fibroblasts (RPFs).
The expression of aldosterone synthase (CYP11B2), mineralocorticoid receptors (MRs), 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), serum- and glucocorticoid-inducible protein kinase 1 (SGK1), and connective tissue growth factor (CTGF) mRNA was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). To determine the role of reactive oxygen species (ROS) induced by aldosterone, an active oxygen assay with several inhibitors was used. The ability of RPFs to produce aldosterone was examined by enzyme immunoassay. Small interfering RNA (siRNA) of SGK1 was transfected into cultured cells using lipofectamine.
CYP11B2, MRs, and 11beta-HSD2 were expressed in RPFs. The release of aldosterone from RPFs into the culture medium was confirmed. Aldosterone increased the expression of SGK1 mRNA via ROS generation. Spironolactone, apocynin, and tempol significantly reduced SGK1 expression. Aldosterone upregulated CTGF transcripts significantly. SGK1 gene silencing suppressed aldosterone-induced CTGF expression.
The local aldosterone system acts directly as a profibrotic factor via ROS-mediated SGK1 in RPFs.
Kidney and Blood Pressure Research 07/2009; 32(3):185-93. · 1.46 Impact Factor
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Shinsaku Matsunaga,
Mitsuhiko Okigaki,
Mitsuo Takeda,
Akihiro Matsui,
Shoken Honsho,
Asako Katsume,
Eigo Kishita,
Jishan Che,
Che Jishan,
Tatsuya Kurihara,
Yasushi Adachi,
Alka Mansukhani,
Miyuki Kobara,
Satoaki Matoba,
Yoshiaki Matoba,
Tetsuya Tatsumi, Hiroaki Matsubara
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ABSTRACT: Fibroblast growth factor receptor (FGFR) is expressed in a variety of cells and is involved in their proliferation/migration/survival. To elucidate FGFR-mediated specific action of vascular endothelial cells (ECs) on myocardial ischemia, we generated endothelium-targeted transgenic mice overexpressing constitutively active FGFR2 using Tie2 promoter (FGFR2-Tg). Infarct size, vessel formation and blood perfusion were significantly improved 28 days after myocardial infarction (MI) in FGFR2-Tg, compared with wild-type mice. Aortic ECs isolated from FGFR-Tg showed a marked increase in migratory capacity and tube formation. These in vitro angiogenic activities were blocked by PI3-kinase inhibitor. Whereas, parameters obtained from echocardiography were already improved at three days after MI. Cardiomyocyte apoptosis at the ischemic border zone was decreased in FGFR2-Tg (32.1%, p < 0.05) and cardiac mRNA expression of FGF2 (basic FGF) was also up-regulated (142%, p < 0.05) at 3 days after MI. 1% oxygen-mediated apoptosis was significantly inhibited in FGFR2-Tg-ECs and this inhibition was abolished by PI3-kinase inhibitor. FGFR2-Tg-ECs exposed to 1% oxygen exhibited enhanced phosphorylation of 416-Tyr-Src, 473-Ser-Akt, and HIF1alpha accumulation. The production of FGF2 was enhanced 2.1-fold in FGFR-Tg-ECs under 1% oxygen via the Src/Akt/HIF1alpha pathway, which induced the peri-vessel migration of vascular smooth muscle cells (VSMCs) and anti-apoptotic effects on VSMCs and cardiomyocytes. FGF receptor signaling in ECs promoted migration, survival and autocrine production of FGF2, leading to reduced infarct size, which is associated with anti-apoptotic action in the early stage and with enhanced angiogenesis in the late stage after MI.
Journal of Molecular and Cellular Cardiology 06/2009; 46(5):663-73. · 5.17 Impact Factor
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Akiko Okazaki,
Yasukiyo Mori,
Midori Nakata,
Taikou Kimura,
Kazuhiro Sonomura,
Chikako Sakoda,
Eiko Matsuoka,
Mami Ishida,
Hideki Yamahara,
Noriko Kishimoto,
Hisako Nakagawa, Hiroaki Matsubara
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ABSTRACT: Peritoneal fibrosis can lead to the discontinuation of continuous ambulatory peritoneal dialysis. The present study investigated the direct effect of aldosterone, which influences tissue fibrosis, and its cellular mechanism using cultured rat peritoneal mesothelial cells (RPMCs).
The expression of aldosterone synthase (CYP11B2), mineralocorticoid receptors, 11beta-hydroxysteroid dehydrogenase 2, serum- and glucocorticoid-inducible protein kinase 1 (SGK1) and connective tissue growth factor (CTGF) was evaluated using reverse transcriptase-polymerase chain reaction and Western blot. The ability of RPMCs to produce aldosterone was examined by enzyme immunoassay. Small interfering RNA of SGK1 was transfected to determine the role of SGK1.
CYP11B2, mineralocorticoid receptors and 11beta-hydroxysteroid dehydrogenase 2 were expressed in RPMCs. The release of aldosterone from RPMCs into the culture medium was confirmed. Stimulation of RPMCs with the addition of aldosterone significantly increased SGK1 expression and phosphorylation and CTGF upregulation, and these effects were completely inhibited by the mineralocorticoid receptor antagonist spironolactone. SGK1 gene silencing abrogated aldosterone-induced CTGF expression.
The local aldosterone system exists and acts directly as a profibrotic factor in the peritoneal mesothelium.
Kidney and Blood Pressure Research 06/2009; 32(3):151-60. · 1.46 Impact Factor
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Koji Ikeda,
Ritsuko Nakano,
Maki Uraoka,
Yusuke Nakagawa,
Masahiro Koide,
Asako Katsume,
Keizo Minamino,
Eri Yamada,
Haruhiko Yamada,
Thomas Quertermous, Hiroaki Matsubara
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ABSTRACT: Endothelial apoptosis is a pivotal process for angiogenesis during embryogenesis as well as postnatal life. By using a retrovirus-mediated signal sequence trap method, we identified a previously undescribed gene, termed ARIA (apoptosis regulator through modulating IAP expression), which regulates endothelial apoptosis and angiogenesis. ARIA was expressed in blood vessels during mouse embryogenesis, as well as in endothelial cells both in vitro and in vivo. ARIA is a unique protein with no homology to previously reported conserved domain structures. Knockdown of ARIA in HUVECs by using small interfering RNA significantly reduced endothelial apoptosis without affecting either cell migration or proliferation. ARIA knockdown significantly increased inhibitor of apoptosis (cIAP)-1 and cIAP-2 protein expression, although their mRNA expression was not changed. Simultaneous knockdown of cIAP-1 and cIAP-2 abolished the antiapoptotic effect of ARIA knockdown. Using yeast 2-hybrid screening, we identified the interaction of ARIA with 20S proteasome subunit alpha-7. Thereafter, we found that cIAP-1 and cIAP-2 were degraded by proteasomes in endothelial cells under normal condition. Overexpression of ARIA significantly reduced cIAP-1 expression, and this reduction was abolished by proteasomal inhibition in BAECs. Also, knockdown of ARIA demonstrated an effect similar to proteasomal inhibition with respect to not only expression but also subcellular localization of cIAP-1 and cIAP-2. In vivo angiogenesis studied by Matrigel-plug assay, mouse ischemic retinopathy model, and tumor xenograft model was significantly enhanced by ARIA knockdown. Together, our data indicate that ARIA is a unique factor regulating endothelial apoptosis, as well as angiogenesis, presumably through modulating proteasomal degradation of cIAP-1 and cIAP-2 in endothelial cells.
Proceedings of the National Academy of Sciences 06/2009; 106(20):8227-32. · 9.68 Impact Factor
