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Hiroyuki Takano

Publications and source records attributed to Hiroyuki Takano.

47 records · Page 3Linked to original sources
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

Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease.

The homeobox transcription factor CSX/NKX2.5, which is a vertebrate homologue of the Drosophila gene tinman, is essential for cardiac development. It is expressed in the early cardiac mesoderm and in heart muscle lineage throughout life. Homozygous deletion of CSX/NKX2.5 causes early embryonic lethality in mice because cardiac development is arrested at the linear heart tube stage. Heterozygous mutation of human CSX/NKX2.5 has been associated with various congenital heart diseases such as atrial septal defect (ASD), ventricular septal defect, tetralogy of Fallot, and tricuspid valve abnormalities, including Ebstein's anomaly. Additionally, CSX/NKX2.5 mutation causes atrioventricular (AV) conduction block with or without associated congenital heart diseases. Ten different heterozygous mutations have been already reported and a new point mutation, which is a C-to-A transition (Cys264ter) at nucleotide 901 of CSX/NKX2.5, results in the production of a truncated protein occurring COOH-terminal to the homeodomain of CSX/NKX2.5. The mutation was found in a patient with familial ASD and first-degree AV block; 4 members from 3 generations had secundum-type ASD and first-degree AV block.

Cysteine↗
PubMed2002

Continuous blockade of L-type Ca2+ channels suppresses activation of calcineurin and development of cardiac hypertrophy in spontaneously hypertensive rats.

We examined whether Ca2+ channel blockers inhibit the activation of the Ca2+-dependent phosphatase calcineurin and the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). We randomly divided 12-week-old SHR into three groups, one each receiving vehicle, bolus injection or continuous infusion of nifedipine (10 mg/kg/day) from 12 to 24 weeks of age. Systolic blood pressure (BP) and heart rate were measured every week after the treatment using the tail-cuff plethysmography method. After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to examinations that included an assay for calcineurin activity in the heart, magnetic resonance imaging (MRI), histology and Northern blot analysis. Continuous infusion of nifedipine consistently reduced BP, whereas bolus injection resulted in a fluctuation of BP. Continuous infusion of nifedipine not only reduced left ventricular mass but also decreased the transverse diameter of cardiomyocytes, interstitial fibrosis and the expression of the atrial natriuretic peptide and brain natriuretic peptide genes in the heart, while bolus injection of nifedipine did not significantly attenuate any of these hypertrophic responses in SHR. The activity of calcineurin in the heart was strongly suppressed by continuous but not bolus infusion of nifedipine in SHR. The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity.

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↗
PubMedDate not supplied

Roles of peroxisome proliferator-activated receptor gamma in cardiovascular disease.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to a nuclear receptor superfamily. PPARs have three isoforms: alpha, beta (or delta), and gamma. It is known that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones (TZDs) and the natural prostaglandin D2 (PGD2) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), have been identified as ligands for PPARgamma. Furthermore, it has become apparent that PPARs are present both in a variety of different cell types and in atherosclerotic lesions and the studies about PPARgamma have been extended. Although activation of PPARgamma appears to have protective effects on atherosclerosis, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular disease. Recent evidence suggests that some benefit from antidiabetic agents, TZDs, may occur independent of increased insulin sensitivity. In this article, we review the latest developments in the PPAR field and summarize the roles of PPARgamma and the actions of PPARgamma ligands in the cardiovascular system.

Animals↗