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Issei Komuro

Publications and source records attributed to Issei Komuro.

At least 145 records · Page 8Linked to original sources
PubMed2003

Leukemia inhibitory factor enhances survival of cardiomyocytes and induces regeneration of myocardium after myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is a leading cause of cardiac morbidity and mortality in many countries; however, the treatment of MI is still limited. METHODS AND RESULTS: We demonstrate a novel gene therapy for MI using leukemia inhibitory factor (LIF) cDNA. We injected LIF plasmid DNA into the thigh muscle of mice immediately after inducing MI. Intramuscular injection of LIF cDNA resulted in a marked increase in circulating LIF protein concentrations. Two weeks later, left ventricular remodeling, such as infarct extent and myocardial fibrosis, was markedly attenuated in the LIF cDNA-injected mice compared with vehicle-injected mice. More myocardium was preserved and cardiac function was better in the LIF-treated mice than in the vehicle-injected mice. Injection of LIF cDNA not only prevented the death of cardiomyocytes in the ischemic area but also induced neovascularization in the myocardium. Furthermore, LIF cDNA injection increased the number of cardiomyocytes in cell cycle and enhanced mobilization of bone marrow cells to the heart and their differentiation into cardiomyocytes. CONCLUSIONS: The intramuscular injection of LIF cDNA may induce regeneration of myocardium and provide a novel treatment for MI.

Animals↗
PubMed2003

Characterization of a novel C. elegans RGS protein with a C2 domain: evidence for direct association between C2 domain and Galphaq subunit.

RGS (regulator of G protein signaling) proteins are GTPase-activating proteins (GAPs) for heterotrimeric G protein alpha subunits and negatively regulate G protein-mediated signal transduction. In this study, we determined the cDNA sequence of a novel Caenorhabditis elegans (C. elegans) RGS protein. The predicted protein, termed C2-RGS, consists of 782 amino acids, and contains a C2 domain and an RGS domain. C2 domains are typically known to be Ca(2+) and phospholipid binding sites, found in many proteins involved in membrane traffic or signal transduction, and most of their biological roles are not identified. To study the function of C2-RGS protein, a series of six truncated versions of C2-RGS were constructed. When the full-length protein of C2-RGS was expressed transiently in AT1a-293T cells, ET-1-induced Ca(2+) responses were strongly suppressed. When each of the mutants with either RGS domain or C2 domain was expressed, the Ca(2+) responses were suppressed moderately. Furthermore, we found that C2 domain of PLC-beta1 also had a similar moderate inhibitory effect. RGS domain of C2-RGS bound to mammalian and C. elegans Galphai/o and Galphaq subunits only in the presence of GDP/AlF(4)(-), and had GAP activity to Galphai3. On the other hand, C2 domains of C2-RGS and PLC-beta1 also bound strongly to Galphaq subunit, in the presence of GDP, GDP/AlF(4)(-), and GTPgammaS, suggesting the stable persistent association between these C2 domains and Galphaq subunit at any stage during GTPase cycle. These results indicate that both the RGS domain and the C2 domain are responsible for the inhibitory effect of the full-length C2-RGS protein on Galphaq-mediated signaling, and suggest that C2 domains of C2-RGS and PLC-beta1 may act as a scaffold module to organize Galphaq and the respective whole protein molecule in a stable signaling complex, both in the absence and presence of stimulus.

Amino Acid Sequence↗
PubMed2003

Cdc42 plays a critical role in assembly of sarcomere units in series of cardiac myocytes.

Cardiomyocyte hypertrophy is observed in various cardiovascular diseases and causes heart failure. We here examined the role of small GTP-binding proteins of Rho family in phenylephrine (PE)-or leukocyte inhibitory factor (LIF)-induced hypertrophic morphogenesis of cultured neonatal rat cardiomyocytes. Both LIF and PE increased cell size of cardiomyocytes. LIF induced an increase in the length/width ratio of cardiomyocytes, while PE did not change the ratio. Adenoviral gene transfer of constitutively active mutants of Cdc42 increased the length/width ratio of cardiomyocytes and dominant negative mutants of Cdc42 conversely inhibited LIF-induced cell-elongation, while mutants of RhoA and Rac1 did not affect the length/width ratio of cardiomyocytes. These results suggest that Cdc42, but not RhoA and Rac1, is involved in LIF-induced sarcomere assembly in series in cardiomyocytes.

Adenoviridae↗
PubMed2003

Roles of cardiac transcription factors in cardiac hypertrophy.

Different cell types, equipped with unique structure and function, synthesize different sets of proteins on the basis of different patterns of gene expression, even though their genomes are identical. Cardiac transcription factors have been reported to control a cardiac gene program and thus to play a crucial role in transcriptional regulation during embryogenesis. Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. In this review, the regulation of a cardiac gene program by cardiac transcription factors is summarized, with an emphasis on their potential role in the generation of cardiac hypertrophy.

Animals↗
PubMed2003

Attenuated defense response and low basal blood pressure in orexin knockout mice.

The perifornical area of the hypothalamus has been known as the center for the defense response, or "fight or flight" response, which is characterized by a concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide (0.1-1 mM in 20 nl), to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice. Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 +/- 8 mmHg in wild type and 92 +/- 3 in knockout) and conscious (125 +/- 6 mmHg in wild type and 109 +/- 2 in knockout) conditions. alpha-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.

Animals↗
PubMed2003

Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes.

Cell transplantation could be a potential therapy for heart damage. Skeletal myoblasts have been expected to be a good cell source for autologous transplantation; however, the safety and efficacy of their transplantation are still controversial. Recent studies have revealed that skeletal muscle possesses the stem cell population that is distinct from myoblasts. To elucidate whether skeletal muscle stem cells can transdifferentiate into cardiomyocytes, we cocultured skeletal muscle cells isolated from transgenic mice expressing green fluorescent protein with cardiomyocytes of neonatal rats. Skeletal muscle-derived cells expressed cardiac-specific proteins such as cardiac troponin T and atrial natriuretic peptide as well as cardiac-enriched transcription factors such as Nkx2E (formerly called Csx/Nkx2.5) and GATA4 by coculture with cardiomyocytes. Skeletal muscle-derived cells also expressed cadherin and connexin 43 at the junctions with neighboring cardiomyocytes. Cardiomyocyte-like action potentials were recorded from beating skeletal muscle-derived cells. Treatment of nifedipine or culture in Ca2+-free media suppressed contraction of cardiomyocytes and inhibited skeletal muscle cells to express cardiac-specific proteins. Cyclic stretch completely restored this inhibitory effect. These results suggest that some part of skeletal muscle cells can transdifferentiate into cardiomyocytes and that direct cell-to-cell contact and contraction of neighboring cardiomyocytes are important for the transdifferentiation.

Action Potentials↗
PubMed2003

Complications of pulmonary vein isolation by catheter ablation evaluated by ECG-gated multislice computed tomography.

As pulmonary vein (PV) isolation by catheter ablation for paroxysmal atrial fibrillation may cause PV luminal stenosis, digital subtraction angiography or magnetic resonance imaging have been used to evaluate the lumen of the PV. Electrocardiogram-gated multislice computed tomography can evaluate the lumen of the PV from any plane desired after acquisition with excellent spatial resolution. It can also evaluate hyperplasia of soft tissue around the lumen of the PV, which cannot be evaluated by digital subtraction angiography, and may thus serve as an indicator of complications or even the effectiveness of this treatment.

Atrial Fibrillation↗
PubMed2003

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats.

OBJECTIVES: The aim of the present study was to determine whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have preventive effects on the development of cardiac hypertrophy and heart failure. BACKGROUND: Statins have been reported to have various pleiotropic effects, such as inhibition of inflammation and cell proliferation. METHODS: Dahl rats were divided into three groups: LS, the rats fed the low-salt diet (0.3% NaCl); HS, the rats fed the high-salt diet (8% NaCl) from the age of 6 weeks; and CERI, the rats fed the high-salt diet with cerivastatin 1 mg/kg/d by gavage from the age of 6 weeks. RESULTS: In HS rats, cardiac function was markedly impaired and all rats showed the signs of heart failure within 17 weeks of age. In CERI rats, cardiac function was better than that of HS and no rats were dead up to 17 weeks of age. The development of cardiac hypertrophy and fibrosis was attenuated, and the number of apoptotic cells and expression of proinflammatory cytokine interleukin (IL)-1beta gene were less as compared with HS rats. Pretreatment of cerivastatin suppressed the adriamycin-induced apoptosis of cultured cardiomyocytes of neonatal rats. CONCLUSIONS: These results suggest that statins have a protective effect on cardiac myocytes and may be useful to prevent the development of hypertensive heart failure.

Animals↗
PubMed2003

Na+/Ca2+ exchanger-deficient mice have disorganized myofibrils and swollen mitochondria in cardiomyocytes.

The Na(+)/Ca(2+) exchanger (NCX1) plays a key role in maintaining Ca(2+) homeostasis in cardiomyocytes. Disruption of Ncx1 gene in mice results in embryonic lethality between embryonic day 9 and 10, with the mice lacking spontaneous heartbeats. We examined the mechanism of lack of heartbeats in Ncx1-deficient mice. Ultrastructual analysis demonstrated that Ncx1-deficient mice showed severe disorganization of myofibrils, a lack of Z-lines and swelling of mitochondria in cardiomyocytes. However, the expressions of cardiac-specific genes including transcription factor genes and contractile protein genes were not changed in Ncx1-deficient mice. Abnormal Ca(2+) handling itself or the lack of heartbeats due to the inactivation of Ncx1 gene may cause the disorganization of myofibrillogenesis. Although NCX1 protein levels were decreased in heterozygous mice, there were no changes in NCX2 and NCX3 protein levels between wild type and heterozygous mice.

Animals↗
PubMed2003

Oxidative stress-induced signal transduction pathways in cardiac myocytes: involvement of ROS in heart diseases.

Reactive oxygen species (ROS) are proposed to contribute to the deterioration of cardiac function in patients with heart diseases. It has been reported that ROS are increased in the failing heart and involved in atherosclerosis, myocardial ischemia/reperfusion injury, and heart failure. Antioxidant enzymes are decreased in the decompensated heart, depressing defense mechanisms against oxidative stress. A variety of proteins, including receptors, ionic channels, transporters, and components of signal transduction pathways, are substrates of oxidation by ROS. ROS also function as signal transduction intermediates to induce transcription factor activation, gene expression, cell growth, and apoptosis. Recently, the upstream and downstream molecules of ROS in signal transduction pathways have been the subjects of intense investigation. These molecules include the mitogen-activated protein kinase family, the Rho family of small GTP binding proteins, the Src family of tyrosine kinases, Ras, and cytokines. The modulation of oxidative stress-induced signaling pathways is effective for preventing the progression of heart diseases.

Animals↗
PubMed2003

Gene expression profile revealed different effects of angiotensin II receptor blockade and angiotensin-converting enzyme inhibitor on heart failure.

Although recent clinical studies have indicated that angiotensin II receptor blocker is as effective in treating heart failure as an angiotensin-converting enzyme inhibitor, it is unknown whether their effects are different. Dahl salt-sensitive rats were treated with an angiotensin-converting enzyme inhibitor benazepril, and an angiotensin II receptor blocker candesartan from 11 weeks old. We examined cardiac geometry and function by echocardiography, and histology and gene expression by high-density oligonucleotide arrays using Affymetrix U34 (Affymetrix, Santa Clara, CA, U.S.A.). Dahl salt-sensitive rats fed a high salt diet showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricle dilation and congestive heart failure by 20 weeks after birth. Although both medications had only a mild antihypertensive effect, they strongly suppressed the development of cardiac hypertrophy, fibrosis and heart failure to the same extent. Gene expression pattern examined by Affymetrix GeneChip (Affymetrix) is quite different between the two drug groups, indicating that angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor prevent heart failure by different mechanisms.

Angiotensin Receptor Antagonists↗
PubMed2003

Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na+/Ca2+ exchanger.

Using Na+/Ca2+ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca2+ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal injury was investigated. Because NCX1(-/-) homozygous mice die of heart failure before birth, we used NCX1(+/-) heterozygous mice. NCX1 protein in the kidney of heterozygous mice decreased to about half of that of wild-type mice. Expression of NCX1 protein in the tubular epithelial cells and Ca2+ influx via NCX1 in renal tubules were markedly attenuated in the heterozygous mice. Ischemia/reperfusion-induced renal dysfunction in heterozygous mice was significantly attenuated compared with cases in wild-type mice. Histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca2+ deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical endothelin-1 localization in necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was performed, the renal functional parameters of both NCX1(+/+) and NCX1(+/-) acute renal failure mice were improved to the same level. These findings strongly support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.

Animals↗
PubMed2003

Endoluminal perspective volume rendering of coronary arteries using electron-beam computed tomography.

Remarkable progress has been made in the treatment of coronary heart diseases because of a variety of new interventional devices, but as each new device or procedure has suitability for a particular type of patient or purpose, patient selection is increasingly important. Endoluminal perspective volume renderings of the coronary arteries of a 70-year-old male with old myocardial infarction and recurrent chest pain were carried out using electron-beam computed tomography. Conventional coronary angiography had revealed significant stenosis of the distal portion of the left anterior descending branch, and subsequent conventional balloon angioplasty had failed to expand the stenotic site. Perspective volume rendering images can distinguish differences in objects and evaluate the cross sectional area of the lumen and the morphology of calcification. In the present patient, a huge mass of calcified plaque occupied most of the lumen at a site corresponding to the angiographic site of stenosis. According to this finding, rotational atherectomy was indicated and had a good outcome. The qualitative information for characterizing and determining the morphology of atherosclerotic plaque provided by perspective volume rendering may be useful in selecting the appropriate intervention.

Aged↗
PubMed2003

Improvement of left ventricular dysfunction during exercise by walking in patients with successful percutaneous coronary intervention for acute myocardial infarction.

A growing body of evidence suggests that walking reduces the incidence of coronary events, so the present study investigated whether walking influences left ventricular function in 30 patients with acute myocardial infarction (AMI) who had undergone successful percutaneous coronary intervention (PCI). The patients were randomly assigned to either a 3-month exercise training program of walking (group W, n=15) or a control group (group C, n=15). At both the beginning and end of the study, patients underwent exercise stress echocardiography to determine left ventricular ejection fraction (LVEF) at rest and during exercise. At baseline, there was no difference in LVEF at rest or during exercise between the two groups. After 3 months, LVEF during exercise was significantly improved compared with at rest in group W (61+/-3% during exercise vs 57+/-5% at rest, p<0.01), whereas no difference was observed between the LVEF at rest and that during exercise in group C (54+/-5% at rest vs 52+/-7% during exercise, NS). Walking may be beneficial for improving left ventricular function during exercise in patients with AMI.

Adult↗
PubMed2003

Impact of change in the price of percutaneous coronary intervention devices on medical expenses.

Percutaneous coronary intervention (PCI) devices are much more expensive in Japan than in the United States, but their prices were reduced in April 2002. This study evaluated the impact of that change in the price of PCI devices on medical expenses. In-hospital costs of 22 consecutive patients who underwent elective single-vessel PCI without a debulking procedure before April 2002 were collected and the in-hospital cost of each patient was recalculated by applying the current prices of the PCI devices and those in the USA. For patients treated with PCI before April 2002, the in-hospital cost was 1,456,375+/-358,781 yen, but when the current price is used, the in-hospital cost is estimated to be 1,355,812 +/-313,237 yen (7% reduction). If the prices of the devices were reduced to those in USA, there would be a 53% reduction (689,417 +/-99,139 yen). Although the change in the price of PCI devices in April 2002 has reduced in-hospital costs, the devices are still much more expensive in Japan than in the USA. Further reduction of the price is required to make PCI more cost-effective.

Angioplasty, Balloon, Coronary↗