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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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ABSTRACT: Although the modulated expression of Dicer is documented upon neoplastic transformation, little is known of the regulation of Dicer expression by environmental stimuli and its roles in the regulation of cellular functions in primary cells. In this study, we found that Dicer expression was downregulated upon serum withdrawal in human umbilical vein endothelial cells (HUVECs). Serum withdrawal induced a time-dependent repression of Dicer expression, which was specifically rescued by vascular endothelial cell growth factor or sphingosine-1-phosphate. When Dicer expression was silenced by short-hairpin RNA against Dicer, the cells were more prone to apoptosis under serum withdrawal, whereas the rate of apoptosis was comparable with control cells in the serum-containing condition. Real-time PCR-based gene expression profiling identified several genes, the expression of which was modulated by Dicer silencing, including adhesion and matrix-related molecules, caspase-3, and nitric oxide synthase 3 (NOS3). Dicer silencing markedly impaired migratory functions without affecting cell adhesion and repressed phosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 in adherent HUVECs. Dicer knockdown upregulated caspase-3 and downregulated NOS3 expression, and serum withdrawal indeed increased caspase-3 and decreased NOS3 expression. Furthermore, the overexpression of Dicer in HUVECs resulted in a marked reduction in apoptosis upon serum withdrawal and a decreased caspase-3 and increased NOS3 expression. The inhibition of NOS activity by Nomega-nitro-L-arginine methyl ester abrogated the effect of Dicer overexpression to rescue the cells from serum withdrawal-induced apoptosis. These results indicated that serum withdrawal decreases Dicer expression, leading to an increased susceptibility to apoptosis through the regulation of caspase-3 and NOS3 expression.
AJP Heart and Circulatory Physiology 11/2008; 295(6):H2512-21. · 3.71 Impact Factor
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ABSTRACT: Skeletal myogenesis is a multistep process by which multinucleated mature muscle fibers are formed from undifferentiated, mononucleated myoblasts. However, the molecular mechanisms of skeletal myogenesis have not been fully elucidated. Here, we identified muscle-restricted coiled-coil (MURC) protein as a positive regulator of myogenesis. In skeletal muscle, MURC was localized to the cytoplasm with accumulation in the Z-disc of the sarcomere. In C2C12 myoblasts, MURC expression occurred coincidentally with myogenin expression and preceded sarcomeric myosin expression during differentiation into myotubes. RNA interference (RNAi)-mediated knockdown of MURC impaired differentiation in C2C12 myoblasts, which was accompanied by impaired myogenin expression and ERK activation. Overexpression of MURC in C2C12 myoblasts resulted in the promotion of differentiation with enhanced myogenin expression and ERK activation during differentiation. During injury-induced muscle regeneration, MURC expression increased, and a higher abundance of MURC was observed in immature myofibers compared with mature myofibers. In addition, ERK was activated in regenerating tissue, and ERK activation was detected in MURC-expressing immature myofibers. These findings suggest that MURC is involved in the skeletal myogenesis that results from modulation of myogenin expression and ERK activation. MURC may play pivotal roles in the molecular mechanisms of skeletal myogenic differentiation.
AJP Cell Physiology 06/2008; 295(2):C490-8. · 3.54 Impact Factor
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ABSTRACT: The existence of skeletal muscle-derived stem cells (MDSCs) has been suggested in mammals; however, the signaling pathways controlling MDSC proliferation remain largely unknown. Here we report the isolation of myosphere-derived progenitor cells (MDPCs) that can give rise to beating cardiomyocytes from adult skeletal muscle. We identified that follistatin, an antagonist of TGF-beta family members, was predominantly expressed in MDPCs, whereas myostatin was mainly expressed in myogenic cells and mature skeletal muscle. Although follistatin enhanced the replicative growth of MDPCs through Smad2/3 inactivation and cell cycle progression, disruption of myostatin did not increase the MDPC proliferation. By contrast, inhibition of activin A (ActA) or growth differentiation factor 11 (GDF11) signaling dramatically increased MDPC proliferation via down-regulation of p21 and increases in the levels of cdk2/4 and cyclin D1. Thus, follistatin may be an effective progenitor-enhancing agent neutralizing ActA and GDF11 signaling to regulate the growth of MDPCs in skeletal muscle.
Biochemical and Biophysical Research Communications 02/2008; 365(4):863-9. · 2.48 Impact Factor
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ABSTRACT: The role of Smads and their specific ligands during cardiomyogenesis in ES cells was examined. Smad2 was activated bimodally in the early and late phases of cardiac differentiation, whereas Smad1 was activated after the middle phase. Nodal and Cripto were expressed in the early stage and then downregulated, whereas transforming growth factor-beta and activin were expressed only in the late phase. Suppression of early Smad2 activation by SB-431542 produced complete inhibition of endodermal and mesodermal induction but augmented neuroectodermal differentiation, followed by poor cardiomyogenesis, whereas inhibition during the late phase alone promoted cardiomyogenesis. Inhibitory effect of Smad2 on cardiomyogenesis in the late phase was mainly mediated by transforming growth factor-beta, and inhibition of transforming growth factor-beta-mediated Smad2 activation resulted in a greater replicative potential in differentiated cardiac myocytes and enhanced differentiation of nonmyocytes into cardiac myocytes. Thus, endogenous Smad2 activation is indispensable for endodermal and mesodermal induction in the early phase. In the late phase, endogenous transforming growth factor-beta negatively regulates cardiomyogenesis through Smad2 activation by modulating proliferation and differentiation of cardiac myocytes.
Circulation Research 08/2007; 101(1):78-87. · 9.49 Impact Factor
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ABSTRACT: We have reported that skeletal myosphere-derived progenitor cells (MDPCs) can differentiate into vascular cells, and that MDPC transplantation into cardiomyopathic hearts improves cardiac function. However, the autocrine/paracrine molecules and underlying mechanisms responsible for MDPC growth have not yet been determined. To explore the molecules enhancing the proliferation of MDPCs, we performed serial analysis of gene expression and signal sequence trap methods using RNA isolated from MDPCs. We identified osteopontin (OPN), a secretory molecule, as one of most abundant molecules expressed in MDPCs. OPN provided a proliferative effect for MDPCs. MDPCs treated with OPN showed Akt activation, and inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway repressed the proliferative effect of OPN. Furthermore, OPN-pretreated MDPCs maintained their differentiation potential into endothelial and vascular smooth muscle cells. These findings indicate an important role of OPN as an autocrine/paracrine molecule in regulating the proliferative growth of muscle-derived angiogenic progenitor cells via the PI3K/Akt pathway.
Biochemical and Biophysical Research Communications 08/2007; 359(2):341-7. · 2.48 Impact Factor
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ABSTRACT: Bone marrow cells have been shown to contribute to neovascularization in ischemic hearts, whereas their impaired maturation to restore the delta-sarcoglycan (delta-SG) expression responsible for focal myocardial degeneration limits their utility to treat the pathogenesis of cardiomyopathy. Here, we report the isolation of multipotent progenitor cells from adult skeletal muscle, based on their ability to generate floating-myospheres. Myosphere-derived progenitor cells (MDPCs) are distinguishable from myogenic C2C12 cells and differentiate into vascular smooth muscle cells and mesenchymal progeny. The mutation in the delta-SG has been shown to develop vascular spasm to affect sarcolemma structure causing cardiomyopathy. We originally generated delta-SD knockdown (KD) mice and transplanted MDPCs into the hearts. MDPCs enhanced neoangiogenesis and restored delta-SG expression in impaired vasculatures through trans-differentiation, leading to improvement of cardiac function associated with paracrine effectors secretion. We propose that MDPCs may be the promising progenitor cells in skeletal muscle to treat delta-sarcoglycan complex mutant cardiomyopathy.
Biochemical and Biophysical Research Communications 02/2007; 352(3):668-74. · 2.48 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs emerging as important post-transcriptional gene regulators. In this study, we examined the role of miR-1, an miRNA specifically expressed in cardiac and skeletal muscle tissue, on the myogenic, osteoblastic, and adipogenic differentiation of C2C12 cells. Upon induction of myogenic differentiation, miR-1 was robustly expressed. Retrovirus-mediated overexpression of miR-1 markedly enhanced expression of muscle creatine kinase, sarcomeric myosin, and alpha-actinin, while the effects on myogenin and MyoD expression were modest. Formation of myotubes was significantly augmented in miR-1-overexpressing cells, indicating miR-1 expression enhanced not only myogenic differentiation but also maturation into myotubes. In contrast, osteoblastic and adipogenic differentiation was not affected by forced expression of miR-1. Thus, the muscle-specific miRNA, miR-1, plays important roles in controlling myogenic differentiation and maturation in lineage-committed cells, rather than functioning in fate determination.
Biochemical and Biophysical Research Communications 01/2007; 350(4):1006-12. · 2.48 Impact Factor
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ABSTRACT: A case of ST-segment elevation provoked by distended stomach conduit is presented. An 83-year-old woman was admitted to our hospital with worsening chest discomfort. She had a previous history of subtotal esophagectomy, which was reconstructed using a stomach conduit in the posterior mediastinum. Electrocardiogram showed ST-segment elevation in the inferior leads and a prominent negative P wave in lead V1. Echocardiography demonstrated normal left ventricular function without regional wall motion abnormality; however, the left atrium and ventricle compressed by a substantially distended stomach conduit was noted. Subsequent angiocardiography revealed no coronary atherosclerotic stenosis and normal contractility of the left ventricle. Chest symptoms resolved soon after nasogastric suction, leading to resolution of electrocardiographic changes. The stomach conduit diminished on following repeated echocardiography. The patient was discharged without any evidence of myocardial infarction. Esophagus disease of the reconstructed stomach conduit should be recognized as a rare but considerable cause for electrocardiographic changes.
International Journal of Cardiology 06/2006; 109(3):411-3. · 7.08 Impact Factor
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ABSTRACT: Sinus cycle length has been reported to fluctuate after a ventricular premature beat (VPB). The purpose of this study was to assess the short-term fluctuations of sinus cycle length in patients with hypertrophic cardiomyopathy (HCM) and prior myocardial infarction (MI).
The relative deviation of RR intervals from the mean of the last two RR intervals preceding a VPB were calculated during the 20 subsequent beats following the VPB from Holter recordings in 92 patients with non-obstructive HCM, 57 patients with prior MI and 54 healthy controls.
In controls, the deviations of the RR intervals were negative for several beats after a VPB and subsequently changed to positive before returning to the baseline. Similar changes in RR intervals following a VPB were exhibited in HCM patients; however, the late positive deviations of RR intervals were more marked than in controls. By contrast, in patients with prior MI, the early negative deviations of RR intervals were smaller compared with controls, and the deviations returned to the baseline without incidence of the positive changes.
Short-term fluctuations in sinus cycle length after a VPB differed exclusively among HCM patients, prior MI patients, and healthy controls.
International Journal of Cardiology 06/2005; 101(2):315-7. · 7.08 Impact Factor
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ABSTRACT: Isolated left venticular noncompaction (IVNC) is a rare congenital heart disease charactrized by a pattern of an excessively prominent trabecular meshwork with deep intertrabecular recesses. Heart rate variability (HRV) has been reported to be impaired in various heart diseases, though little is known regarding HRV in adult patients with IVNC.
We measured spectral components of HRV using fast Fourier transformation of 24-h Holter recordings in 10 adult patients with IVNC, 40 patients with myocardial infarction (MI), 40 patients with hypertrophic cardiomyopathy (HCM) and 40 healthy controls.
The low frequency component and the high frequency component of HRV were lower in IVNC patients tahn those in controls (265 +/- 213 ms(2) vs. 469 +/- 195 ms(2), p < 0.01; 80 +/- 51 ms(2) vs. 185 +/- 126 ms(2), p < 0.01). Furthermore, 3 IVNC patients with a previous history of heart failure exhibited more decreased HRV (low frequency, 75 +/- 56 ms(2); high frequency, 39 +/- 18 ms(2)). Contrary, the ratio of low frequency to high frequency component was higher in patients with IVNC than controls (3.5+/-0.5 vs. 3.2 +/- 0.3, p < 0.05). The degree of impaired HRV was severest in MI patients, intermediate in IVNC patients and mildest in HCM patients compared with controls.
HRV is impaired in adult patients with IVCN, especially in patients with a previous history of heart failure, suggesting vagal withdrawal or sympathetic enhancement. HRV in IVNC adults is less impaired than in MI patients, and more impaired than in HCM patients of our cohort.
International Journal of Cardiology 04/2005; 99(1):147-50. · 7.08 Impact Factor
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ABSTRACT: The present study examined whether the very low frequency (VLF) power of heart rate variability (HRV) is predictive of clinical prognosis in patients with congestive heart failure (CHF).
The study recruited 54 consecutive CHF patients with emergency admission because of exacerbation of pulmonary congestion. Holter monitoring was performed after improvement of pulmonary congestion. The frequency components of HRV were calculated in the frequency domain (VLF, low frequency (LF), high frequency (HF), total power (TP) and the ratio of LF to HF power). The left ventricular ejection fraction was calculated, and plasma brain natriuretic peptide (BNP) and norepinephrine were also measured at discharge. Within a mean follow-up period of 19.8 +/- 11.7 months, 18 patients experienced cardiovascular events; 7 patients died and 11 patients required rehospitalization because of worsening of CHF. In univariate analysis, diabetes mellitus (DM), BNP and New York Heart Association (NYHA) functional class were significant as risk factors for cardiac events. VLF power, LF power and TP were the strong predictors for cardiac events in HRV. In multivariate analysis, VLF power predicted cardiac events independently of LF power, TP, DM, BNP and NYHA functional class (chi-square=6.24, p=0.01).
VLF power is an independent risk predictor in patients with CHF.
Circulation Journal 05/2004; 68(4):343-7. · 3.77 Impact Factor
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ABSTRACT: An 82-year-old woman was referred to the authors' institution because of an electrocardiographic abnormality mimicking acute myocardial infarction. Left ventriculography showed apical wall hypokinesis and basal wall hyperkinesis. Coronary angiography revealed no organic stenosis. Three days earlier, she was told she had renal cancer. She was diagnosed as having "takotsubo" cardiomyopathy. She underwent early and delayed Tc-99m tetrofosmin single photon emission computed tomography (SPECT). The early SPECT images revealed homogeneous tracer uptake in the left ventricle, but the delayed images revealed decreased uptake in the apical wall. Reverse redistribution of Tc-99m tetrofosmin was observed in this patient with "takotsubo" cardiomyopathy.
Clinical Nuclear Medicine 10/2003; 28(9):757-9. · 3.67 Impact Factor
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New England Journal of Medicine 08/2003; 349(3):258. · 53.30 Impact Factor
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ABSTRACT: Short-term fluctuations in sinus cycle length after a single ventricular premature complex (VPC) have attracted considerable interest and has been termed heart rate turbulence (HRT). The onset and slope of HRT have each been reported to be independent and powerful predictors of clinical prognosis in patients with myocardial infarction (MI), but there are no data available for patients with hypertrophic cardiomyopathy (HCM). Thus the present study analyzed the 2 HRT variables to determine their prognostic value in HCM patients. Holter monitoring data were obtained from 104 HCM patients, 44 MI patients and 56 normal controls, from which singular VPCs followed by >or=20 normal sinus beats were isolated and the HRT onset and slope were automatically calculated. HRT onset and slope were abnormal in MI patients, but not in HCM patients, as compared with normal control subjects (onset -1.1+/-2.9, -2.1+/-3.4, -1.4+/-5.1%; slope 10.6 +/-8.6, 18.0+/-13.9, 16.6+/-9.7 ms/beat, respectively). During the follow-up period of 27+/-10 months, 7 HCM patients and 10 MI patients either died from cardiac death or were hospitalized for congestive heart failure. In MI patients, HRT onset was higher and the HRT slope was lower in patients with cardiac events than in patients without (onset 1.1+/-2.7 vs -1.7+/-2.7%, p=0.011; slope 5.7+/-4.3 vs 12.0+/-9.0 ms/beat, p=0.028). In HCM patients, however, the HRT onset and slope were similar between patients with and without cardiac events (onset -2.0+/-2.0 vs -2.1 +/-3.5%, p=0.98; slope 18.1+/-10.9 vs 18.0+/-14.0 ms/beat, p=0.68). In conclusion, unlike MI patients, the HRT variables in selected HCM patients were not abnormal and failed to predict the clinical prognosis.
Circulation Journal 08/2003; 67(7):601-4. · 3.77 Impact Factor
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ABSTRACT: The YUMIKO catheter (Goodman, Nagoya, Japan) was recently developed for a left internal mammary artery (IMA) angiography with a right radial or brachial approach. The present authors experienced an interesting case where the YUMIKO catheter was useful for a right IMA angiography via a right brachial artery. A 53-year-old man with bilateral IMA grafts underwent follow-up coronary angiography via a right brachial artery. Native coronary artery and left IMA angiography were performed without difficulty using the Judkins Right and Left and YUMIKO catheters. Angiography of the right IMA was attempted with the Judkins Right catheter and IMA catheter, resulting in a nonselective angiogram with poor imaging. The YUMIKO catheter, however, enabled smooth cannulation to the right IMA and provided good images of the selective right IMA angiography.
International Journal of Cardiovascular Interventions 02/2003; 5(2):98-101.
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ABSTRACT: The existence of skeletal muscle-derived stem cells (MDSCs) has been suggested in mammals; however, the signaling pathways controlling MDSC proliferation remain largely unknown. Here we report the isolation of myosphere-derived progenitor cells (MDPCs) that can give rise to beating cardiomyocytes from adult skeletal muscle. We identified that follistatin, an antagonist of TGF-β family members, was predominantly expressed in MDPCs, whereas myostatin was mainly expressed in myogenic cells and mature skeletal muscle. Although follistatin enhanced the replicative growth of MDPCs through Smad2/3 inactivation and cell cycle progression, disruption of myostatin did not increase the MDPC proliferation. By contrast, inhibition of activin A (ActA) or growth differentiation factor 11 (GDF11) signaling dramatically increased MDPC proliferation via down-regulation of p21 and increases in the levels of cdk2/4 and cyclin D1. Thus, follistatin may be an effective progenitor-enhancing agent neutralizing ActA and GDF11 signaling to regulate the growth of MDPCs in skeletal muscle.
Biochemical and Biophysical Research Communications.
