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Teruhiko Toyo-oka

Publications and source records attributed to Teruhiko Toyo-oka.

12 recordsLinked to original sources
PubMed2006

Focalized contractile impairment at hypertrophied myocardium proven in consideration of wall stress in patients with hypertrophic cardiomyopathy.

In hypertrophic cardiomyopathy (HCM) a hyperkinetic state is sometimes observed in spite of impaired systolic function in the hypertrophied myocardium. The aim of the present study was to determine the mechanism of this paradox. Seventeen patients with HCM and 10 normal subjects underwent cine magnetic resonance (MR) imaging to measure percent systolic wall thickening and percent fractional shortening. The ratio of systolic radial wall stress of the LV at the hypertrophied myocardium over that at the nonhypertrophied myocardium was evaluated to describe the focal advantageous condition for wall thickening. The ratio was 0.66 +/- 0.36 at the start of contraction and 0.78 +/- 0.31 at early-systole, indicating consistently smaller radial wall stress at the hypertrophied myocardium. Although the condition for contraction was favorable (a ratio less than 1.00), percent systolic wall thickening at the hypertrophied myocardium (23.0 +/- 11.8%) was smaller than that at the nonhypertrophied myocardium (70.5 +/- 32.3%). Smaller end-diastolic dimension (HCM group; 45.2 +/- 4.2 mm, reference group; 48.9 +/- 4.1 mm, P = 0.04) with a statistically identical value of systolic decrease in intraventricular dimension (HCM group; 19.7 +/- 3.9 mm, reference group; 18.9 +/- 3.2 mm, P = 0.60) yielded high percent fractional shortening in patients with HCM (43.5 +/- 7.6%). Although contractile impairment was proven at the hypertrophied region with low radial wall stress in the HCM group, the smaller end-diastolic dimension in this group resulted in high percent fractional shortening.

Cardiomyopathy, Hypertrophic↗
PubMed2004

RNAi induction and activation in mammalian muscle cells where Dicer and eIF2C translation initiation factors are barely expressed.

Dicer plays an important role in the course of RNA interference (RNAi), i.e., it digests long double-stranded RNAs into 21-25 nucleotide small-interfering RNA (siRNA) duplexes functioning as sequence-specific RNAi mediators. In this study, we investigated the expression levels of Dicer and eIF2C1 approximately 4, which, like Dicer, appear to participate in mammalian RNAi, in various mouse tissues. Results indicate that the levels of eIF2C1 approximately 4 as well as Dicer are lower in skeletal muscle and heart than in other tissues. To see if RNAi could occur under such a condition with low levels of expression of Dicer and eIF2C1 approximately 4, we examined RNAi activity in mouse skeletal muscle fibers. The results indicate that RNAi can be induced by synthetic siRNA duplexes in muscle fibers. We further examined RNAi activity during myogenic differentiation of mouse C2C12 cells. The data indicate that although the expression levels of Dicer and eIF2C1 approximately 4 decrease during the differentiation, RNAi can be induced in the cells. Altogether, the data presented here suggest that muscle cells retain the ability to induce RNAi, although Dicer and eIF2C1 approximately 4 appear to be barely expressed in them.

Animals↗
PubMed2004

Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.

BACKGROUND: The efficacy and optimum dose of beta-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a beta-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF. METHODS: After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class. RESULTS: Carvedilol therapy achieved dose-dependent improvement of all end points (P for linear trend, range.002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization (P range,.024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events. CONCLUSIONS: In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

Adrenergic beta-Antagonists↗
PubMed2004

[A new paradigm for the progression of advanced heart failure].

To clarify the precise mechanism for the progression of advanced heart failure (AdHF), we assessed the scheme in two HF models, using (I) TO-2 strain hamsters sharing common genetic and clinical features to human families with the delta-sarcoglycan (SG) gene mutation and (II) administration of a high-dose (HD) of isoproterenol (Isp) to normal rats. Delta-SG is a component in dystrophin (Dys)-related proteins that stabilize the sarcolemma (SL) during repeated heart beats. In TO-2, we followed time course of hemodynamics, immunostaining and Western blotting of Dys and in situ SL permeability by Evans blue uptake with or without the gene therapy. Dys was age-dependently translocated from the SL to myoplasm (MP) where the SL instability accompanied the fragmentation of Dys. By gene therapy to supplement the normal delta-SG gene in hearts in vivo, we found that Dys translocation was selectively improved in cardiomyocytes expressing the delta-SG transgene, where the SL fragility was ameliorated. Most importantly, the survival period of the animals was prolonged. Furthermore, Dys but not delta-SG was also time-dependently shifted with a HD of Isp from the SL to MP and fragmented, while delta-SG was preserved intact. We present a novel paradigm that disruption of Dys, but not delta-SG per se, leads to AdHF irrespective of hereditary or acquired origin.

Animals↗
PubMed2003

Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development.

Several prospective clinical studies have indicated that hydroxymethylglutaryl-coenzyme A reductase inhibitors, statins, prevent cardiovascular events in part through their antiinflammatory properties. Because inflammation is positively and negatively regulated by T helper (Th) 1 cells and Th2 cells, respectively, we examined the effects of statins on the Th polarization in vitro and in vivo. Here we demonstrated that the statins tested, ie, cerivastatin, simvastatin, lovastatin, and atorvastatin, promoted Th2 polarization through both inhibition of Th1 development and augmentation of Th2 development of CD4+ T cells primed in vitro with anti-CD3 antibody and splenic antigen-presenting cells. Cerivastatin exerted most potent effect on modulation of Th1/Th2 development, and the effect was completely abrogated by an addition of mevalonate. Consistent with in vitro experiments, cerivastatin treatment decreased IFN-gamma production of lymph node cells from mice immunized with ovalbumin emulsified in complete Freund's adjuvant, indicating that Th1 development is also suppressed in an in vivo proinflammatory environment. In this murine model, cerivastatin significantly reduced mesangial matrix expansion of glomeruli in the kidney and attenuated proteinuria. The decrease of glomerular sclerosis by cerivastatin treatment was positively related to the suppression of interferon (IFN)-gamma-producing Th1 response in draining lymph node cells. Hence, these findings strongly suggest that statins' inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury.

Animals↗
PubMed2003

Decrease in sarcoglycans and dystrophin in failing heart following acute myocardial infarction.

OBJECTIVE: Genetic defects in several sarcoglycans (SGs) and dystrophin (Dys) play a critical role in cardiomyopathy. The present study was designed to determine whether changes in SGs and Dys might occur in animals with chronic heart failure (CHF) induced by acute myocardial infarction (AMI), which have no genetic defects. METHODS: AMI was induced by the left coronary artery ligation (CAL) in rats. The hemodynamic parameters of the 2- and 8-week CAL (2w- and 8w-CAL) rats were measured and the myocardial SGs, Dys, calpain, and calpastatin levels were determined by the Western blot method. Myocardial calpain-like protease activity was evaluated as caseinolysis activity. RESULTS: Increases in left ventricular end-diastolic pressure (LVEDP) and right ventricular systolic pressure, and a decrease in +/-dP/dt were observed at the 2nd week, whereas cardiac output index (COI) was preserved. In contrast, the 8w-CAL rats showed a further increment in LVEDP with low COI. alpha-SG of the viable left ventricle (LV), and septum (Sep) of the 8w-CAL rat decreased (60-70% of the control). The alpha- and beta-SGs of the right ventricle (RV) of the 2w- and 8w-CAL rats were reduced, while gamma- and delta-SGs in the three regions did not change significantly. Dys in the viable LV and RV of the 8w-CAL rat decreased (75% of the control). The amount of m-calpain in the three regions of the 2w- and 8w-CAL rats increased (140-200% of the control), whereas the endogenous calpain inhibitor, calpastatin, did not change significantly. The in vitro degradation studies using purified m-calpain or cytosolic fractions of the 8w-CAL rat heart suggested a reduction in SGs and Dys by calpain. CONCLUSION: The results suggest that a decrease in SGs and Dys may play an important role in the pathophysiology of CHF following AMI.

Animals↗
PubMed2003

Targeting of iNOS with antisense DNA plasmid reduces cytokine-induced inhibition of osteoblastic activity.

Proinflammatry cytokines, tumor necrosis factor-alpha combined with interleukin-1beta, induce excessive production of nitric oxide (NO) and its cytotoxic metabolite peroxynitrite (ONOO-) via inducible nitric oxide synthase (iNOS) in murine osteoblasts. In this study, to properly estimate the effects of antisense DNA of iNOS on osteoblastic activity, we produced transformed cell lines with antisense plasmid that specifically targets the iNOS gene for potential long-lasting inhibition. Transformed antisense cell lines were identified by 1) the detection of antisense transcripts, 2) the attenuated expression of iNOS protein, 3) the reduction of NO synthase activity, and 4) the level of NO production. These cell lines targeting iNOS, which showed decreased production of both NO and ONOO-, prevented the inhibition of osteoblastic differentiation as was assayed by the mRNA expression of type I collagen, alkaline phosphatase, osteocalcin, and Core binding factor in the presence of proinflammatory cytokines. Present results indicate that the antisense DNA plasmid of iNOS is potent to reduce the cytokine-induced inhibition of osteoblastic activity.

Alkaline Phosphatase↗
PubMed2002

Nonselective cation currents regulate membrane potential of rabbit coronary arterial cell: modulation by lysophosphatidylcholine.

BACKGROUND: The effects of lysophosphatidylcholine (LPC) on electrophysiological activities and intracellular Ca2+ concentration ([Ca2+]i) were investigated in coronary arterial smooth muscle cells (CASMCs). METHODS AND RESULTS: The patch clamp techniques and Ca2+ measurements were applied to cultured rabbit CASMCs. The membrane potential was -46.0+/-5.0 mV, and LPC depolarized it. Replacement of extracellular Na+ with NMDG+ hyperpolarized the membrane and antagonized the depolarizing effects of LPC. In Na+-, K+-, or Cs+-containing solution, the voltage-independent background current with reversal potential (E(r)) of approximately +0 mV was observed. Removal of Cl- failed to affect it. When extracellular cations were replaced by NMDG+, E(r) was shifted to negative potentials. La3+ and Gd3+ abolished the background current, but nicardipine and verapamil did not inhibit it. In Na+-containing solution, LPC induced a voltage-independent current with E(r) of approximately +0 mV concentration-dependently. Similar current was recorded in K+- and Cs+-containing solution. La3+ and Gd3+ inhibited LPC-induced current, but nicardipine and verapamil did not inhibit it. In cell-attached configurations, single-channel activities with single-channel conductance of approximately 32pS were observed when patch pipettes were filled with LPC. LPC increased [Ca2+]i as the result of Ca2+ influx, and La3+ completely antagonized it. CONCLUSIONS: These results suggest that (1) nonselective cation current (I(NSC)) contributes to form membrane potentials of CASMCs and (2) LPC activates I(NSC), resulting in an increase of [Ca2+]i. Thus, LPC may affect CASMC tone under various pathophysiological conditions such as ischemia.

Animals↗
PubMed2002

Cell density and growth-dependent down-regulation of both intracellular calcium responses to agonist stimuli and expression of smooth-surfaced endoplasmic reticulum in MC3T3-E1 osteoblast-like cells.

A two-dimensional intracellular Ca(2+) ([Ca(2+)](i)) imaging system was used to examine the relationship between [Ca(2+)](i) handling and the proliferation of MC3T3-E1 osteoblast-like cells. The resting [Ca(2+)](i) level in densely cultured cells was 1.5 times higher than the [Ca(2+)](i) level in sparsely cultured cells or in other cell types (mouse fibroblasts, rat vascular smooth muscle cells, and bovine endothelial cells). A high resting [Ca(2+)](i) level may be specific for MC3T3-E1 cells. MC3T3-E1 cells were stimulated with ATP (10 microM), caffeine (10 mM), thapsigargin (1 microM), or ionomycin (10 microM), and the effect on the [Ca(2+)](i) level of MC3T3-E1 cells was studied. The percentage of responding cells and the degree of [Ca(2+)](i) elevation were high in the sparsely cultured cells and low in densely cultured cells. The rank order for the percentage of responding cells and magnitude of the Ca(2+) response to the stimuli was ionomycin > thapsigargin = ATP > caffeine and suggests the existence of differences among the various [Ca(2+)](i) channels. All Ca(2+) responses in the sparsely cultured MC3T3-E1 cells, unlike in other cell types, disappeared after the cells reached confluence. Heptanol treatment of densely cultured cells restored the Ca(2+) response, suggesting that cell-cell contact is involved with the confluence-dependent disappearance of the Ca(2+) response. Immunohistological analysis of type 1 inositol trisphosphate receptors and electron microscopy showed distinct expression of inositol trisphosphate receptor proteins and smooth-surfaced endoplasmic reticulum in sparsely cultured cells but reduced levels in densely cultured cells. These results indicate that the underlying basis of confluence-dependent [Ca(2+)](i) regulation is down-regulation of smooth-surfaced endoplasmic reticulum by cell-cell contacts.

3T3 Cells↗
PubMed2002

Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters.

BACKGROUND: The TO-2 hamster is an animal model of dilated cardiomyopathy (DCM). It has genetic and clinical features in common with humans who carry the gene deletion or mutation of the delta-sarcoglycan (SG) gene, a component in dystrophin-related proteins (DRP). DRP stabilise the sarcolemma during cardiac contraction. We performed in vivo gene therapy of the TO-2 hamster, whose heart is defective in all four SG proteins, to determine its potential as a model for therapy for DCM. In addition to the hereditary origin, heart failure is aggravated by treatment with catecholamines and ameliorated by the administration of some kinds of beta-antagonist both in humans and in TO-2 hamsters. METHODS: Gene therapy for DCM was achieved by supplementing the delta-SG gene with rAAV vector and intramurally delivering rAAV-delta-SG into the cardiac apex and left ventricle. RESULTS: This treatment resulted in: (i) a sustained and non-pathogenic expression of both the transcript and transgene of delta-SG and all other SG proteins; (ii) improvement to both morphological and physiological deterioration; and (iii) rescued prognosis compared with untreated TO-2 hamsters, and TO-2 hamsters transfected with reporter gene alone. Another acute heart-failure model was prepared by high-dose isoproterenol treatment in Wistar rats, which resulted in: (i) translocation of dystrophin, but not delta-SG, from the cardiac sarcolemma to the myoplasm; and (ii) fragmentation of dystrophin, probably due to the activation of endogenous protease(s) or proteasome(s) that contributed to muscular dystrophy-like degeneration occurring specifically in cardiomyocytes. CONCLUSIONS: Both the TO-2 hamster and the isoproterenol-treated Wistar rat models commonly experience disruption of dystrophin or DRP. Targeting the responsible gene with the use of a potent vector may provide a novel strategy for the treatment of advanced heart failure.

Journal Article↗
PubMed2002

The relationship between changes in normal-range systolic blood pressure and cognitive function in middle-aged healthy women.

Little is known about the effect of normal-range blood pressure (BP) on cognitive function. In previous studies investigating the relationship between BP and cognitive function in elderly subjects, underlying cerebrovascular damage has complicated the interpretation of results. To reveal the relationship between BP levels that were within an absolutely normal range and cognitive function, we examined cognitive function in normotensive, healthy middle-aged women. BP levels were measured on three separate occasions at 1-month intervals, and the subjects exhibiting normotension (< 140/90 mmHg) throughout the evaluation period were recruited as normotensive subjects. Cognitive function was assessed using subtests of the Wechsler Adult Intelligence Scale-Revised. The study demonstrated that, among the subtests examined, the scores on the Digit Symbol Test, an index of psychomotor performance, had a significant correlation with normotensive-range systolic blood pressure (SBP) (r=-0.51, p<0.05); this relation was negative-that is, higher but still normal-range SBP levels were associated with impaired Digit Symbol Test scores. In addition, the relationship adjusted by age and educational level was also significant (partial correlation = -0.56, p<0.05). In contrast, diastolic BP was not related to the Digit Symbol Test (r = -0.33, p = 0.13). Furthermore, the Digit Symbol Test was not influenced by blood glucose or serum cholesterol levels. These findings suggested that, even within the normotensive range, lower levels of SBP might be protective against impairment of psychomotor speed in middle-aged women.

Aging↗