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Toshio Nagai

Publications and source records attributed to Toshio Nagai.

34 records · Page 2Linked to original sources
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

The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARs have three isoforms, alpha, beta (or delta) and gamma. It has been conceived that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones and natural prostaglandin D(2) (PGD(2)) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), have been identified as ligands for PPARgamma. Following demonstration that PPARgamma is present in a variety of cell types, further study of PPARgamma has been conducted. Although activation of PPARgamma appears to have beneficial effects on atherosclerosis and heart failure, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular diseases. Recent evidence suggests that some benefit from the antidiabetic agents known as thiazolidinediones may occur through PPARgamma-independent mechanisms. In this review, we report on the latest developments concerning the study of PPARs and summarize the roles of the PPARgamma-dependent pathway in cardiovascular diseases.

Animals↗
PubMed2003

Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies.

The concept and clinical implication of left ventricular remodeling have been gradually extended. Cardiac remodeling plays important roles in the progression of cardiovascular diseases including myocardial infarction, valvular heart diseases, myocarditis, and dilated cardiomyopathy. In addition to cardiac myocytes, fibroblasts, extracellular matrix proteins and coronary vasculature are also involved in the remodeling process. Cardiac remodeling is associated with alterations of many mediators such as neurohumoral factors, cytokines, enzymes, ion channels, oxidative stress and mechanical stress. Although remodeling is initially an adaptive response to maintain normal cardiac function, it gradually becomes maladaptive and leads to progressive decompensation. Recent research has attempted to elucidate underlying molecular mechanisms of cardiac remodeling and to develop novel therapeutic strategies for heart failure. The modulation of remodeling process is effective for preventing the progression of heart failure.

Adaptation, Physiological↗
PubMed2003

Pleiotropic effects of cytokines on acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction.

Many cytokines have been reported to be increased in human and animal models with cardiovascular diseases. Myocardial infarction (MI) is accompanied with an inflammatory reaction which induces cardiac dysfunction and remodeling. The inflammatory reaction has been investigated in animal models of MI or myocardial ischemia-reperfusion injury. The mechanisms by which cytokine cascade is activated in the infarcted myocardium have been recently elucidated. Several hematopoietic growth factors including interleukin-3 (IL-3), IL-6, granulocyte-macrophage colony-stimulating factors (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) have been reported to be positive regulators of granulopoiesis and act at different stages of myeloid cell development. G-CSF plays a critical role in regulation of proliferation, differentiation, and survival of myeloid progenitor cells. G-CSF also causes a marked increase in the release of hematopoietic stem cells (HSCs) into the peripheral blood circulation, a process termed mobilization. Although cardiac myocytes have been considered as terminally differentiated cells, it has been recently reported that there are many proliferating cardiac myocytes after MI in human heart. After it was demonstrated that bone marrow stem cells (BMSCs) can differentiate into cardiac myocytes, myocardial regeneration has been widely investigated. Recently, G-CSF has been reported to improve cardiac function and reduces mortality after acute MI. Although the mechanism by which G-CSF ameliorates cardiac dysfunction is not fully understood, there is the possibility that G-CSF may regenerate cardiac myocytes and blood vessels through mobilization of BMSCs. In the future, cytokine-mediated regeneration therapy may become to be a novel therapeutic strategy for MI.

Acute Disease↗
PubMed2002

Reactive oxygen species induce cardiomyocyte apoptosis partly through TNF-alpha.

Many studies have indicated that oxidative stress induces apoptosis in cardiomyocytes, but its mechanism remains unknown. We examined whether tumor necrosis factor-alpha (TNF-alpha) is involved in oxidative stress-induced cardiomyocyte apoptosis. Pretreatment with anti-TNF-alpha antibody significantly decreased the number of H(2)O(2)-induced TUNEL-positive cardiomyocytes. Expression of TNF-alpha gene was upregulated by H(2)O(2), and H(2)O(2) mildly but significantly increased the concentration of TNF-alpha in the culture medium. Although neither low dose of H(2)O(2) nor TNF-alpha induced apoptosis, stimulation with H(2)O(2) and TNF-alpha synergistically increased apoptosis. These results suggest that oxidative stress induces apoptosis of cardiac myocytes partly through TNF-alpha.

Animals↗
PubMed2002

Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are transcription factors of the nuclear receptor superfamily. It has been reported that the thiazolidinediones, which are antidiabetic agents and high-affinity ligands for PPARgamma, regulate growth of vascular cells. In the present study, we examined the role of PPARgamma in angiotensin II (Ang II)-induced hypertrophy of neonatal rat cardiac myocytes and in pressure overload-induced cardiac hypertrophy of mice. METHODS AND RESULTS: Treatment of cultured cardiac myocytes with PPARgamma ligands such as troglitazone, pioglitazone, and rosiglitazone inhibited Ang II-induced upregulation of skeletal alpha-actin and atrial natriuretic peptide genes and an increase in cell surface area. Treatment of mice with a PPARgamma ligand, pioglitazone, inhibited pressure overload-induced increases in the heart weight-to-body weight ratio, wall thickness, and myocyte diameter in wild-type mice and an increase in the heart weight-to-body weight ratio in heterozygous PPARgamma-deficient mice. In contrast, pressure overload-induced increases in the heart weight-to-body weight ratio and wall thickness were more prominent in heterozygous PPARgamma-deficient mice than in wild-type mice. CONCLUSIONS: These results suggest that the PPARgamma-dependent pathway is critically involved in the inhibition of cardiac hypertrophy.

Actins↗
PubMed2002

Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart.

Csx/Nkx2-5, which is essential for cardiac development of the embryo, is abundantly expressed in the adult heart. We here examined the role of Csx/Nkx2-5 in the adult heart using two kinds of transgenic mice. Transgenic mice that overexpress a dominant negative mutant of Csx/Nkx2-5 (DN-TG mice) showed degeneration of cardiac myocytes and impairment of cardiac function. Doxorubicin induced more marked cardiac dysfunction in DN-TG mice and less in transgenic mice that overexpress wild type Csx/Nkx2-5 (WT-TG mice) compared with non-transgenic mice. Doxorubicin induced cardiomyocyte apoptosis, and the number of apoptotic cardiomyocytes was high in the order of DN-TG mice, non-transgenic mice, and WT-TG mice. Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death. These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype and in protecting the heart from stresses including doxorubicin.

Animals↗
PubMed2002

Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload.

The Na+-Ca2+ exchanger (NCX) on the plasma membrane is thought to be the main calcium extrusion system from the cytosol to the extracellular space in many mammalian excitable cells, including cardiac myocytes. However, the pathophysiological role of NCX in the heart is still unclear because of the lack of known specific inhibitors of NCX. To determine the role of NCX in cardiac contraction and the development of cardiac hypertrophy, we imposed pressure overload on the heart of heterozygous NCX knockout (KO) mice by constricting transverse aorta, and examined cardiac function and morphology 3 wk after operation. Although there was no difference in cardiac function between sham-operated KO mice and sham-operated wild-type (WT) mice, KO mice showed higher left ventricular pressure and better systolic function than WT mice in response to pressure overload. Northern blot analysis revealed that mRNA levels of sarcoplasmic reticulum Ca2+-ATPase were reduced by pressure overload in left ventricles of WT but not of KO mice. However, hypertrophic changes with interstitial fibrosis were more prominent in KO mice than WT mice. These results suggest that reduction of NCX results in supernormalized cardiac function and causes marked cardiac hypertrophy in response to pressure overload.

Animals↗
PubMed2002

Integrins play a critical role in mechanical stress-induced p38 MAPK activation.

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.

Animals↗
PubMed2002

Inhibitory molecules in signal transduction pathways of cardiac hypertrophy.

Cardiac hypertrophy is induced by a variety of diseases, such as hypertension, valvular diseases, myocardial infarction, and endocrine disorders. Although cardiac hypertrophy may initially be a beneficial response that normalizes wall stress and maintains normal cardiac function, prolonged hypertrophy is a leading cause of heart failure and sudden death. A number of studies have elucidated molecules responsible for the development of cardiac hypertrophy, including the mitogen-activated protein (MAP) kinases pathway, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and calcium/calmodulin-dependent protein phosphatase calcineurin pathway. These molecules may be targets for therapies designed to prevent the progression of cardiac hypertrophy. Numerous studies have focused on characterization of the intracellular signal transduction molecules that promote cardiac hypertrophy in order to clarify the molecular mechanisms, but there have been only a few reports on the inhibitory regulators of hypertrophic response. Recently, several molecules have attracted much attention as endogenous inhibitory regulators of cardiac hypertrophy. Enhancement of these inhibitory regulators would also seem to be a potential approach for the pharmacological treatment of hypertrophy. In this review, we summarize the inhibitory molecules of cardiac hypertrophy.

Animals↗
PubMed2002

Molecular and cellular mechanisms of mechanical stress-induced cardiac hypertrophy.

Congestive heart failure is one of the major issues for cardiologists. Since cardiac hypertrophy deteriorates into heart failure, it is important to elucidate the mechanisms of cardiac hypertrophy. Hemodynamic overload, namely mechanical stress, is a major cause for cardiac hypertrophy. Mechanical stress induces various hypertrophic responses such as activation of phosphorylation cascades of many protein kinases, expression of specific genes and an increase in protein synthesis. During this process, secretion and production of vasoactive peptides such as angiotensin II and endothelin-1, are increased and play critical roles in the induction of these hypertrophic responses. Recently, a Ca2+ dependent protein kinase, CaMK, and a Ca2+ dependent protein phosphatase, calcineurin, have attracted great attention as critical molecules that induce cardiac hypertrophy. In this review, we described the mechanisms by which mechanical stress induces cardiac hypertrophy, especially focusing on the role of calcineurin in the development of cardiac hypertrophy.

Angiotensin II↗
PubMedDate not supplied

Stretch-modulation of second messengers: effects on cardiomyocyte ion transport.

In cardiomyocytes, mechanical stress induces a variety of hypertrophic responses including an increase in protein synthesis and a reprogramming of gene expression. Recently, the calcium signaling has been reported to play an important role in the development of cardiac hypertrophy. In this article, we report on the role of the calcium signaling in stretch-induced gene expression in cardiomyocytes. Stretching of cultured cardiomyocytes up-regulates the expression of brain natriuretic peptide (BNP). Intracellular calcium-elevating agents such as the calcium ionophore A23187, the calcium channel agonist BayK8644 and the sarcoplasmic reticulum calcium-ATPase inhibitor thapsigargin up-regulate BNP gene expression. Conversely, stretch-induced BNP gene expression is suppressed by EGTA, stretch-activated ion channel inhibitors, voltage-dependent calcium channel antagonists, and long-time exposure to thapsigargin. Furthermore, stretch increases the activity of calcium-dependent effectors such as calcineurin and calmodulin-dependent kinase II, and inhibitors of calcineurin and calmodulin-dependent kinase II significantly attenuated stretch-induced hypertrophy and BNP expression. These results suggest that calcineurin and calmodulin-dependent kinase II are activated by calcium influx and subsequent calcium-induced calcium release, and play an important role in stretch-induced gene expression during the development of cardiac hypertrophy.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗