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Yodo Tamaki,
Yoshitaka Iwanaga,
Shinichiro Niizuma,
Tsuneaki Kawashima,
Takao Kato,
Yasutaka Inuzuka,
Takahiro Horie,
Hanako Morooka,
Toru Takase,
Yasumitsu Akahashi,
Kazuhiro Kobuke,
Koh Ono, Tetsuo Shioi,
Søren P Sheikh,
Noona Ambartsumian,
Eugene Lukanidin,
Taka-Aki Koshimizu,
Shunichi Miyazaki,
Takeshi Kimura
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ABSTRACT: OBJECTIVES: Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. METHODS AND RESULTS: In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53 downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. CONCLUSION: These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.
Journal of Molecular and Cellular Cardiology 01/2013; · 5.17 Impact Factor
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Yasuhiro Hamatani,
Naritatsu Saito,
Junichi Tazaki,
Masahiro Natsuaki,
Kentaro Nakai,
Takeru Makiyama,
Yasuhiro Sasaki,
Masao Imai,
Shin Watanabe, Tetsuo Shioi,
Takeshi Kimura,
Kanji Inoue
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ABSTRACT: Percutaneous transcatheter mitral valvuloplasty is the indicated treatment of choice for symptomatic native mitral valve stenosis, but there have been limited reports of successful procedures of balloon valvuloplasty for bioprosthetic mitral valve stenosis. We present the case of a 62-year-old woman suffering from progressive dyspnea due to bioprosthetic mitral valve stenosis. The measured mean pressure gradient across the mitral valve was 30 mmHg and the mitral valve area was 0.73 cm(2). Redoing mitral replacement was considered high risk and was refused by the patient. Percutaneous balloon valvuloplasty was performed with an Inoue balloon catheter inflated to 20 mm. The patient's symptoms immediately improved after the procedure, with no procedure-related complications. The mean pressure gradient across the valve decreased to 19 mmHg, and the mitral valve area increased to 1.21 cm(2) in postprocedural echocardiography. We conducted a literature search and identified 26 cases of balloon valvuloplasty for degenerated bioprosthetic valves. Of these, 14 cases were bioprosthetic mitral valves, and the results were favorable. However, more case reports are required to establish an evidence base for future expert recommendation of balloon valvuloplasty of prosthetic mitral valve. Meanwhile, balloon valvuloplasty will serve a niche role in highly selected patients with prosthetic mitral valve stenosis.
Heart and Vessels 11/2012; · 2.05 Impact Factor
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ABSTRACT: Heart failure is a typical age-associated disease. However, the mechanism by which heart function declines and heart failure increases in association with age is not clear. Recent advances in basic science clarify several important mechanisms of aging. The mechanisms identified are likely to serve as substrates by which heart function declines and predisposes elderly people to heart failure. One such mechanism is insulin/insulin-like growth factor (IGF)-1 signaling. Suppression of insulin/IGF-1 signaling prevents cardiac aging associated with improved protein homeostasis in the heart. However, the role of insulin/IGF-1 signaling in heart diseases is likely to be pleiotropic, and both protective and sensitizing effects have been described in different contexts. Reduction in function of extra-cardiac organs is likely to be another important mechanism by which heart failure increases with aging, since heart failure is a multiple organ system disease.
Journal of Cardiology 10/2012; · 1.28 Impact Factor
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ABSTRACT: Conventional exercise training (ET) for elderly patients with heart failure (HF) includes low-intensity stretching and gait training. The effects of 2 types of low-intensity ET - machine-assisted cycling and conventional ET - on exercise capacity and endothelial function of elderly patients with HF was investigated in the present study.
Twenty-seven elderly patients with HF (mean age: 79.5 years) were randomly assigned to either a machine-assisted cycling group or a conventional ET group. At baseline and after 2 weeks of ET, all patients were tested for 6-minute walk distance (6MWD) and digital reactive hyperemia-peripheral arterial tonometry (RH-PAT). After 2 weeks of ET, a significant increase in 6MWD was observed in both groups with no significant difference between the groups. RH-PAT index significantly increased in patients aged ≤80 (1.55±0.33 to 1.93±0.62, P=0.035) and a trend toward increase in RH-PAT index in the machine-assisted cycling group was observed (1.59±0.52 to 1.93±0.63, P=0.053), although no change was observed in the conventional ET group. In the multivariate model, patients' age and machine-assisted cycling were associated with the increases in RH-PAT index (P<0.05).
Machine-assisted cycling appeared to be as effective as conventional ET on exercise capacity in elderly patients with HF. Additionally, machine-assisted cycling has the potential to improve endothelial function in these patients.
Circulation Journal 05/2012; 76(8):1889-94. · 3.77 Impact Factor
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Shinichiro Niizuma,
Yasutaka Inuzuka,
Junji Okuda,
Takao Kato,
Tsuneaki Kawashima,
Yodo Tamaki,
Yoshitaka Iwanaga,
Yuki Yoshida,
Rie Kosugi,
Kayo Watanabe-Maeda,
Yoji Machida,
Shingo Tsuji,
Hiroyuki Aburatani,
Tohru Izumi,
Toru Kita,
Takeshi Kimura, Tetsuo Shioi
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ABSTRACT: Insulin/insulin-like growth factor-1 (IGF-1) signaling plays an important role in many biological processes. The class IA isoform of phosphoinositide 3-kinase (PI3K) is an important downstream effector of the insulin/IGF-1 signaling pathway. The aim of this study is to examine the effect of persistent activation of PI3K on gene expression and markers of cellular senescence in murine hearts.
Transgenic mice expressing a constitutively active PI3K in a heart-specific manner were analyzed at the ages of 3 and 20 months. Effects of persistent activation of PI3K on gene expression were comprehensively analyzed using microarrays.
Upon comprehensive gene expression profiling, the genes whose expression was increased included those for several heat shock chaperons. The amount and nuclear localization of a forkhead box O (FOXO) protein was increased. In addition, the gene expression of insulin receptor substrate-2 decreased, and that of phosphatase and tensin homolog deleted on chromosome ten (PTEN) increased, suggesting that the persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling. The expression of markers of cellular senescence, such as senescence-associated beta-galactosidase activity, cell cycle inhibitors, proinflammatory cytokines, and lipofuscin, did not differ between old wild-type and caPI3K mice.
The persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling pathway in a transgenic mouse line. Markers of cellular senescence were not changed in the aged mutant mice.
Life sciences 02/2012; 90(15-16):619-28. · 2.56 Impact Factor
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Tsuneaki Kawashima,
Yasutaka Inuzuka,
Junji Okuda,
Takao Kato,
Shinichiro Niizuma,
Yodo Tamaki,
Yoshitaka Iwanaga,
Akira Kawamoto,
Michiko Narazaki,
Tetsuya Matsuda,
Souichi Adachi,
Genzou Takemura,
Toru Kita,
Takeshi Kimura, Tetsuo Shioi
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ABSTRACT: Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD(+)-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.
Journal of Molecular and Cellular Cardiology 09/2011; 51(6):1026-36. · 5.17 Impact Factor
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Takao Kato,
Shinichiro Niizuma,
Yasutaka Inuzuka,
Tsuneaki Kawashima,
Junji Okuda,
Akira Kawamoto,
Yodo Tamaki,
Yoshitaka Iwanaga,
Tomoyoshi Soga,
Toru Kita,
Takeshi Kimura, Tetsuo Shioi
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ABSTRACT: BACKGROUND: Cachexia, namely body wasting, is a common complication in cases of congestive heart failure (CHF). Although, neurohumoral and immune abnormalities are associated with the condition, precisely how the imbalance of catabolism and anabolism is responsible for the wasting process is not known. METHODS: We analyzed markers of cachexia in Dahl salt-sensitive rats which show marked hypertension with preserved systolic function at 11weeks and CHF at 17-19weeks of age. We also analyzed the change in hepatic metabolism associated with CHF since liver plays a central role in the systemic regulation of catabolism and anabolism. RESULTS: In CHF rats, a failure to grow was observed and blood hepatic protein levels were decreased associated with increased blood proinflammatory cytokine levels, indicating that Dahl rats serve as a model of cardiac cachexia. Food intake was reduced, and blood sugar and insulin levels were decreased. Despite the apparent fasting condition, blood fatty acid levels were decreased and triglycerides levels were increased. In CHF rats, liver incorporated more glucose, the gene expression related to gluconeogenesis was decreased, the gene expression related to lipogenesis was increased, and the triglyceride content of the liver was increased. The paradoxical production of triglycerides synthesis in fasting rats was associated with a proinflammatory response in liver. CONCLUSIONS: The Dahl salt-sensitive rat can be used as a model of cardiac cachexia. The cachexia was associated with abnormal hepatic metabolism that might work as a maladaptive response during the progression of CHF.
International journal of cardiology 08/2011; · 7.08 Impact Factor
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Masahiro Natsuaki,
Yutaka Furukawa,
Takeshi Morimoto,
Yoshihisa Nakagawa,
Masaharu Akao,
Koh Ono, Tetsuo Shioi,
Satoshi Shizuta,
Ryuzo Sakata,
Hitoshi Okabayashi,
Noboru Nishiwaki,
Tatsuhiko Komiya,
Satoru Suwa,
Takeshi Kimura
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ABSTRACT: Among hemodialysis (HD) patients, those who have diabetes have poorer cardiovascular outcomes than non-diabetic patients, but the impact of diabetes on cardiovascular outcomes has not been fully elucidated in HD patients undergoing coronary revascularization.
We identified 375 HD patients (203 diabetes, 172 non-diabetes) and 9,006 patients without HD (3,455 diabetes, 5,551 non-diabetes) in the database of the CREDO-Kyoto registry of patients undergoing their first coronary revascularization. In non-HD patients, significantly higher risks of death (10.8% vs. 7.7%, P < 0.0001; adjusted hazard ratio (HR) 1.29, P < 0.0001) and major adverse cardiovascular events (MACE), a composite of death, myocardial infarction and stroke (18.8% vs. 13.3%, P < 0.0001; HR 1.36, P < 0.0001) were seen in diabetic patients than in non-diabetic patients through 4-year follow-up. Analysis in HD patients showed that the duration of HD before first coronary revascularization was significantly shorter in diabetic patients than in non-diabetic patients (median interval: 858 vs. 2,216 days, P < 0.0001). In contrast to the results in non-HD patients, the risks of death (41.9% vs. 39.1%, P=0.75; HR 0.98, P=0.93) and MACE (45.6% vs. 45.8%, P=0.83; HR 0.87, P=0.50) after first revascularization were comparable between diabetic and non-diabetic HD patients. There were significant interactions between HD and diabetes for death and for MACE.
HD patients who require coronary revascularization have extremely poor outcomes irrespective of concomitant diabetes.
Circulation Journal 06/2011; 75(7):1616-25. · 3.77 Impact Factor
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Hiroki Shiomi,
Toshihiro Tamura,
Shunichiro Niki,
Tomohisa Tada,
Junichi Tazaki,
Masanao Toma,
Koh Ono, Tetsuo Shioi,
Takeshi Morimoto,
Masaharu Akao,
Yutaka Furukawa,
Yoshihisa Nakagawa,
Takeshi Kimura
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ABSTRACT: The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) score was proposed as a method to evaluate the complexity of coronary anatomy. However, the reproducibility of assessment for the SYNTAX score in unprotected left main coronary artery (ULMCA) disease has not yet been adequately evaluated. The purpose of this study is to assess inter- and intra-observer variability for the assessment of the SYNTAX score in patients undergoing ULMCA stenting in daily clinical practice.
The SYNTAX score of 101 consecutive patients who underwent ULMCA stenting with sirolimus-eluting stent was independently assessed by 2 experienced interventional cardiologists. One of the 2 cardiologists evaluated all the cases again 6 months after the initial assessment. The κ value for inter-observer variability in estimating the SYNTAX score was 0.62 according to the dichotomized analysis (≥ 33, < 33) and 0.58 according to the tertile analysis (< 23, 23 ≤ - < 33, ≥ 33), while the intra-observer variability was 0.78 and 0.69, respectively. Patients with a high SYNTAX score (≥ 33, n = 55) compared with those with low or intermediate score (< 33, n = 46) had a significantly higher rate of target-lesion revascularization (TLR) of the ULMCA lesion at 2 years (24% vs. 4.4%, P = 0.01).
Both inter- and intra-observer variability for estimating the SYNTAX score were within an acceptable range and a high SYNTAX score showed a higher rate of TLR in patients undergoing ULMCA stenting in daily clinical practice.
Circulation Journal 03/2011; 75(5):1130-7. · 3.77 Impact Factor
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Circulation Journal 02/2011; 75(2):268-9. · 3.77 Impact Factor
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Takao Kato,
Shinichiro Niizuma,
Yasutaka Inuzuka,
Tsuneaki Kawashima,
Junji Okuda,
Yodo Tamaki,
Yoshitaka Iwanaga,
Michiko Narazaki,
Tetsuya Matsuda,
Tomoyoshi Soga,
Toru Kita,
Takeshi Kimura, Tetsuo Shioi
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ABSTRACT: Congestive heart failure (CHF) is associated with a change in cardiac energy metabolism. However, the mechanism by which this change is induced and causes the progression of CHF is unclear.
We analyzed the cardiac energy metabolism of Dahl salt-sensitive rats fed a high-salt diet, which showed a distinct transition from compensated left ventricular hypertrophy to CHF. Glucose uptake increased at the left ventricular hypertrophy stage, and glucose uptake further increased and fatty acid uptake decreased at the CHF stage. The gene expression related to glycolysis, fatty acid oxidation, and mitochondrial function was preserved at the left ventricular hypertrophy stage but decreased at the CHF stage and was associated with decreases in levels of transcriptional regulators. In a comprehensive metabolome analysis, the pentose phosphate pathway that regulates the cellular redox state was found to be activated at the CHF stage. Dichloroacetate (DCA), a compound known to enhance glucose oxidation, increased energy reserves and glucose uptake. DCA improved cardiac function and the survival of the animals. DCA activated the pentose phosphate pathway in the rat heart. DCA activated the pentose phosphate pathway, decreased oxidative stress, and prevented cell death of cultured cardiomyocytes.
Left ventricular hypertrophy or CHF is associated with a distinct change in the metabolic profile of the heart. DCA attenuated the transition associated with increased energy reserves, activation of the pentose phosphate pathway, and reduced oxidative stress.
Circulation Heart Failure 02/2010; 3(3):420-30. · 6.29 Impact Factor
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Yasutaka Inuzuka,
Junji Okuda,
Tsuneaki Kawashima,
Takao Kato,
Shinichiro Niizuma,
Yodo Tamaki,
Yoshitaka Iwanaga,
Yuki Yoshida,
Rie Kosugi,
Kayo Watanabe-Maeda,
Yoji Machida,
Shingo Tsuji,
Hiroyuki Aburatani,
Tohru Izumi,
Toru Kita, Tetsuo Shioi
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ABSTRACT: Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging.
We analyzed age-associated changes in murine heart and the manner in which suppression of the p110alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart.
Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.
Circulation 10/2009; 120(17):1695-703. · 14.74 Impact Factor
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Takehiro Ogata,
Tomomi Ueyama,
Koji Isodono,
Masashi Tagawa,
Naofumi Takehara,
Tsuneaki Kawashima,
Koichiro Harada,
Tomosaburo Takahashi, Tetsuo Shioi,
Hiroaki Matsubara,
Hidemasa Oh
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ABSTRACT: We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.
Molecular and cellular biology 06/2008; 28(10):3424-36. · 6.06 Impact Factor
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ABSTRACT: Myosin-induced autoimmune myocarditis of rats is a model of human dilated cardiomyopathy. Resveratrol is a natural polyphenol found in grapes and wine that is reported to have cardioprotective and immunomodulatory effects.
To examine the effect of resveratrol on myocarditis, vehicle or resveratrol (50 mg/kg per day) was administered to cardiac myosin immunized rats 1 day before the immunization. At 14 days after immunization, resveratrol had preserved cardiac function of myosin-immunized rats according to echocardiographic analysis. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.8-fold compared with unimmunized rats, and resveratrol attenuated the heart weight increase. Resveratrol significantly decreased cellular infiltration, fibrosis, and expression of inflammatory cytokines in the myocardium. Expressions of antioxidant genes were increased in myosin-immunized hearts, and resveratrol decreased those expressions. Resveratrol also attenuated myocarditis 21 days after immunization. SIRT1, a potential effector of resveratrol, was increased in the myocardium of myosin-immunized rats compared with unimmunized rats. The SIRT1 protein was localized mainly in infiltrating mononuclear cells.
Resveratrol significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis. Resveratrol may be a therapeutic modality for myocarditis.
Circulation Journal 04/2007; 71(3):397-404. · 3.77 Impact Factor
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ABSTRACT: Diabetes mellitus is an independent risk factor for heart failure. Diabetes mellitus causes other age-related cardiovascular diseases. We assessed the hypothesis that hearts from diabetic animals are associated with accelerated aging processes. We also examined the effect of an angiotensin II receptor blocker (ARB) on the expression of senescence-associated molecules.
We administered an ARB (candesartan 10 mg/kg per day) or saline to diabetic db/db or control db/+ mice. The treatment was started when mice were 10-weeks-old, and continued for 15 weeks. Systolic function was impaired in db/db mice and candesartan improved cardiac function. The amount of phosphorylated Akt and S6 was decreased in saline-treated db/db mice, and candesartan treatment partially preserved phosphorylation. The amount of p21, p27, p53 or Rb was increased in the heart tissue of saline treated db/db mice. Candesartan treatment completely suppressed the increases of p21, p27, p53 and Rb.
An ARB improved cardiac function of diabetic animals, and this was accompanied by decreases of senescence-associated molecules in the myocardium. ARB may be a modality for heart failure patients with diabetes mellitus.
Circulation Journal 05/2006; 70(4):482-8. · 3.77 Impact Factor
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ABSTRACT: Alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin (POMC) derivative, is a neuropeptide with potent anti-inflammatory properties that inhibits tissue injury in a wide array of inflammation models.
To determine if alpha-MSH is involved in the development of congestive heart failure (CHF) with the specific aim of examining its peripheral source and one of the mechanisms.
The circulating levels of alpha-MSH were measured in 115 patients with CHF using a double-antibody radioimmunoassay. To determine one of the sources of circulating alpha-MSH, human peripheral blood mononuclear cells (PBMC) were stimulated with lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha. Furthermore, to clarify one of the functions of alpha-MSH, PBMC were cultured in the presence or absence of alpha-MSH.
Plasma levels of alpha-MSH were significantly higher in NYHA class II patients with CHF than in control subjects (p<0.0001). A significant correlation was found between the levels of alpha-MSH and high-sensitive testing for C-reactive protein in patients with CHF (r=0.41, p<0.0005). PBMC stimulated with LPS or TNF-alpha released alpha-MSH in a concentration-dependent manner. alpha-MSH inhibited LPS-induced TNF-alpha production, and alpha-MSH simultaneously augmented production of interleukin (IL)-10 by PBMC.
Circulating alpha-MSH was increased in patients with CHF. Inflammatory response induced alpha-MSH production in cultured human PBMC. Treatment of alpha-MSH could modify the immunobalance between inflammatory and anti-inflammatory responses in cultured PBMC. These findings suggest that alpha-MSH may play an important role in the pathophysiology of CHF.
Internal Medicine 02/2006; 45(7):429-34. · 0.94 Impact Factor
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ABSTRACT: Myosin-induced autoimmune myocarditis in rats is a model of human dilated cardiomyopathy. Rapamycin is a potent immunosuppressant and specifically inactivates the mammalian target of rapamycin (mTOR). To examine the role of mTOR in autoimmune myocarditis, we administered rapamycin to rats immunized with cardiac myosin. Phosphorylation of p70 ribosomal S6 kinase 1 (S6K1), a target of mTOR, was increased by 6.9 fold in the heart tissue of myosin immunized rats. Rapamycin (2 mg/kg/day) completely suppressed S6K1 and S6 phosphorylation. The amount of interleukin-1beta, interferon-gamma, interleukin-2, or tumor necrosis factor-alpha mRNA in the heart tissue was markedly increased in myosin-immunized rats, and rapamycin significantly attenuated the cytokine gene expressions. Rapamycin improved the survival of the rats and preserved cardiac function. The plasma level of brain natriuretic peptide increased by 4.7 fold in myosin-immunized rats, and rapamycin attenuated the increase in plasma brain natriuretic peptide. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.81 +/- 0.06 fold compared with vehicle-treated unimmunized rats, and rapamycin suppressed the increase in heart weight. Rapamycin decreased the cellular infiltration and fibrosis of the myocardium. The amount of phosphorylated S6 was increased in the infiltrating mononuclear cells in vehicle-treated myosin-immunized rats. Rapamycin significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis.
International Heart Journal 06/2005; 46(3):513-30. · 1.16 Impact Factor
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ABSTRACT: This study examined the role of angiotensin II (Ang-II) in a murine model of viral myocarditis.
Ang-II plays an important role in the pathophysiology of various cardiovascular disorders. However, the role of Ang-II in inflammatory heart diseases is not known.
Four-week-old wild-type (WT) and Ang-II type 1 receptor (AT(1)R) knockout (KO) mice were inoculated with the encephalomyocarditis virus (EMCV). Survival, histopathology, expression of proinflammatory cytokines, and activity of nuclear factor-kappa B (NF-kB) in the heart were examined.
The 14-day survival was significantly increased in KO compared with WT mice. Histopathologic scores for myocardial necrosis (0.86 +/- 0.69 vs. 2.44 +/- 0.88, p < 0.01) and cellular infiltration (0.86 +/- 0.38 vs. 2.33 +/- 0.50, p < 0.01) were lower in KO than in WT mice. The expression of tumor necrosis factor-alpha (TNF-alpha) was increased 43.2-fold, that of interleukin-1-beta (IL-1-beta) 45.8-fold, and the activity of NF-kB 2.24-fold by EMCV inoculation in WT mice (each p < 0.01), but not in KO mice (5.9-fold, 6.3-fold, and 1.12-fold, respectively, each p = NS). The AT(1)R blocker also significantly attenuated the expression of proinflammatory cytokines and the activation of NF-kB in virus-inoculated WT mice. Intravenous Ang-II injection enhanced the activation of NF-kB (2.28-fold, p < 0.01) and increased the expression of TNF-alpha (2.31-fold, p < 0.01) and IL-1-beta (2.45-fold, p < 0.01) in heart tissue of WT but not KO mice.
These results indicate that the AT(1)R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II via the NF-kB/cytokine pathway.
Journal of the American College of Cardiology 01/2004; 42(11):2000-6. · 14.16 Impact Factor
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ABSTRACT: This study was designed to examine the effects of carvedilol in a murine model of viral myocarditis induced by encephalomyocarditis virus (EMCV) infection.
Cytokines play an important role in the pathophysiology of viral myocarditis. Catecholamines influence the production of cytokines via beta-adrenergic receptors, suggesting that beta-adrenergic blockers could modulate the production of cytokines and exert a therapeutic effect in viral myocarditis by blocking the beta-stimulating action of endogenous catecholamines. In clinical trials, the third-generation, nonselective beta-blocker carvedilol was the first among several beta-blockers to reduce mortality in heart failure. However, the effects of carvedilol in acute viral myocarditis and on cytokine production are unknown.
This study compared the effects of carvedilol, the selective beta(1)-blocker metoprolol, and the nonselective beta-blocker propranolol in a murine model of viral myocarditis induced by EMCV.
Carvedilol improved the 14-day survival of the animals, attenuated myocardial lesions on day 7, and increased myocardial levels of interleukin (IL)-12 and interferon (IFN)-gamma, whereas reducing myocardial virus replication. Propranolol also attenuated myocardial lesions, but to a lesser extent, and increased IL-12 and IFN-gamma levels. Metoprolol had no effect in this model. Encephalomyocarditis virus infection increased plasma catecholamine levels.
These results suggest that by blocking the beta(2)-stimulating effects of catecholamines, carvedilol exerts some of its beneficial effects by increasing the production of IL-12 and IFN-gamma. Carvedilol may be effective in patients with viral myocarditis by boosting IL-12 and IFN-gamma production.
Journal of the American College of Cardiology 02/2003; 41(2):340-5. · 14.16 Impact Factor
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ABSTRACT: ObjectivesThis study was designed to examine the effects of carvedilol in a murine model of viral myocarditis induced by encephalomyocarditis virus (EMCV) infection.BackgroundCytokines play an important role in the pathophysiology of viral myocarditis. Catecholamines influence the production of cytokines via β-adrenergic receptors, suggesting that β-adrenergic blockers could modulate the production of cytokines and exert a therapeutic effect in viral myocarditis by blocking the β-stimulating action of endogenous catecholamines. In clinical trials, the third-generation, nonselective β-blocker carvedilol was the first among several β-blockers to reduce mortality in heart failure. However, the effects of carvedilol in acute viral myocarditis and on cytokine production are unknown.MethodsThis study compared the effects of carvedilol, the selective β1-blocker metoprolol, and the nonselective β-blocker propranolol in a murine model of viral myocarditis induced by EMCV.ResultsCarvedilol improved the 14-day survival of the animals, attenuated myocardial lesions on day 7, and increased myocardial levels of interleukin (IL)-12 and interferon (IFN)-γ, whereas reducing myocardial virus replication. Propranolol also attenuated myocardial lesions, but to a lesser extent, and increased IL-12 and IFN-γ levels. Metoprolol had no effect in this model. Encephalomyocarditis virus infection increased plasma catecholamine levels.ConclusionsThese results suggest that by blocking the β2-stimulating effects of catecholamines, carvedilol exerts some of its beneficial effects by increasing the production of IL-12 and IFN-γ. Carvedilol may be effective in patients with viral myocarditis by boosting IL-12 and IFN-γ production.
Journal of the American College of Cardiology.
