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At least 1,063 records · Page 59Linked to original sources
PubMed2003

Multiprotein bridging factor 1 cooperates with c-Jun and is necessary for cardiac hypertrophy in vitro.

Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Cardiomyocyte hypertrophy is characterized by increased cell size and altered gene expression. By differential-display polymerase chain reaction and Western blotting we found that the transcriptional coactivator MBF1 was upregulated during hypertrophy in cardiomyocyte cultures. Furthermore, MBF1 protein level increased in two animal models of hypertrophy, angiotensin II treatment and aortic banding. MBF1 antisense oligodeoxynuclotides blocked phenylephrine-induced hypertrophy, suggesting MBF1 plays a key role in hypertrophic growth. In contrast, overexpression of MBF1 potentiated the hormone-induced response of the atrial natriuretic peptide promoter. MBF1 overexpressed by transient transfection cooperated with the transcription factor c-Jun in activation of transcription but not with GATA4. MBF1 and c-Jun induced the activity of a transiently transfected atrial natriuretic peptide promoter, whereas neither MBF1 nor c-Jun could induce the promoter alone. Moreover, MBF1 bound to c-Jun in vitro. These data suggest that MBF1 is a transcriptional coactivator of c-Jun regulating hypertrophic gene expression. Inhibitor studies suggested that MBF1 activates the atrial natriuretic peptide promoter independently of the calcineurin and CaMK signaling pathways. Our results indicate that MBF1 participates in hormone-induced cardiomyocyte hypertrophy and activates hypertrophic gene expression as a coactivator of c-Jun.

3T3 Cells↗
PubMed1984

Unchanged myosin kinase activity in hypertrophied rat heart.

The decrease in myosin ATPase activity observed in cardiac hypertrophy induced by cardiac overload has been related to an isoenzymic redistribution of myosin. To test the hypothesis of an additional regulation of myosin ATPase through light chain phosphorylation, we measured the myosin kinase activity together in sham-operated and 50% to 100% hypertrophied rat hearts. The myosin kinase were purified approximately 600 fold with 6% yield by ion exchange chromatography and calmodulin-affinity chromatography. The presence of very important levels of proteolytic activity in the rat heart resulted in a partial loss of the myosin kinase calmodulin-dependency. The major component from both myosin kinase purified fractions was a 63 kdaltons protein. The protein content was identical in myosin kinase purified fractions from sham-operated and hypertrophied hearts. The calmodulin-dependent activity of myosin kinase, assayed in the presence of 0.1 mM Ca2+ and 10(-6) M calmodulin (about 6.6 nmol P X min-1 X mg-1), was identical in sham-operated and 50% to 100% hypertrophied hearts. Thus, myosin kinase specific activity, in these conditions, was unchanged in rat heart chronic hypertrophy. This result suggests that no direct functional relationship exists between the enzymatic properties of myosin and myosin kinase during the chronic phase of cardiac hypertrophy.

Adenosine Triphosphatases↗
PubMed1984

Three-dimensional characteristics of the intramyocardial microvasculature of hypertrophied human hearts.

The three-dimensional architecture of the intramyocardial microvasculature was demonstrated in hypertrophied human hearts using Evan's method: scanning electron microscopic observation of the cardiac muscle chemically digested by hydrochloric acid and collagenase. Twenty autopsied hearts, which had already been fixed in 10% formalin, were investigated, including 17 hypertrophied hearts (mean cardiac weight, 587 g) and three control hearts (mean cardiac weight, 238 g). The luminal surfaces of the arterioles were characterized by the coiled arrangement of their smooth muscle cells. The structure of these vessels was not significantly different in hypertrophied and normal hearts. The capillaries showed great changes in the hypertrophied muscle: capillaries running on the body of the myofibres, in loop form on disorganized myofibres, and protruding into myofibres and/or probably penetrating through them. These features indicated an increase in the ratio of capillary/myofibre in hypertrophied human hearts. In hypertrophied hearts the venules had a more developed system than normal hearts, but without change in their basic architecture.

Adult↗
PubMed1995

Adaptational response in transcription factors during development of myocardial hypertrophy.

Cardiac hypertrophy is characterized, among others, by the molecular events which selectively activate the expression of genes for contractile proteins within individual myocardial cells. As such, myosin light chain 2 (MLC-2), which is upregulated in the hypertrophic state in both rat and human, serves as a marker for hypertrophy. In an attempt to investigate the gene regulatory mechanisms of this phenomenon, we tested the hypothesis that certain transcription factors are directly involved in the development of cardiac hypertrophy by demonstrating the presence of cardiac tissue-specific regulatory elements in the 5'-flanking region of the MLC-2 promoter and testing them in the gel mobility shift assay for their binding activity to nuclear proteins from hypertrophied and normal cardiac tissue. In nuclear extracts from the ventricular tissues of the spontaneously hypertensive rat (SHR), distinctive changes in two families of activator proteins, the A/T-rich DNA-binding transcription factors, myocyte enhancer factor (MEF-2) and CArG-binding factor, manifested in a developmentally dictated manner paralleling the evolution of cardiac hypertrophy in these animals. Extracts isolated from brains and skeletal muscle tissues from the same animals did not exhibit the changes in binding activity. Also, the changes were not apparent when a distal negative regulatory element (CSS), which confers cardiac-specific expression, was tested in gel mobility shift assays. The ubiquitous TATA-binding proteins remained unchanged in comparing SHR with the control strain WKY in the same assay. These data support the notion that the expression of specific transcription factors is modulated in response to hypertrophy related signals which execute changes at the gene level effecting the enrichment of certain contractile proteins in an effort discrete and estranged from the basal transcription machinery.

Adaptation, Physiological↗
PubMed1980

Cardiac septal hypertrophy in hyperinsulinemic infants.

One infant with nesidioblastosis, and five of 18 infants of diabetic mothers had echocardiographically determined septal hypertrophy (greater than or equal to 6 mm). No correlation was found between the septal hypertrophy and the presence of hypocalcemia, polycythemia, birth asphyxia, or other observed clinical findings. All of the infants with septal hypertrophy, however, had profound hypoglycemia shortly after birth in contrast to those infants without septal hypertrophy. Macrosomic IDM have intrauterine hyperglycemia and hyperinsulinemia. The presence of profound neonatal hypoglycemia is consistent with the metabolic effects of significant neonatal hyperinsulinemia which is also present in the fetus. Infants with nesidioblastosis also have fetal hyperinsulinemia. Recent investigations have suggested an important role for insulin in the developing heart since it is rich in insulin receptors and contains marked insulin degrading capacity. Although fetal hyperglycemia has been suggested as the cause of septal hypertrophy in IDM, we hypothesize that fetal hyperinsulinemia contributes directly to the spinal hypertrophy.

Cardiomegaly↗
PubMed2003

Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy.

The aim of this study is to investigate the effect of berberine on catecholamine level (adrenaline and noradrenaline) in rats with experimental cardiac hypertrophy. Cardiac hypertrophy(CH) was induced by suprarenal abdominal aorta constriction, and the drugs were administered for 8 weeks starting from 4 weeks after surgery. The degree of cardiac hypertrophy was determined by heart and left ventricular weight. The level of adrenaline(AD) and noradrenaline(NA) was detected by HPLC. The data showed that in the CH model rats, the level of plasma and left ventricular tissue AD, and the level of NA in plasma were higher than that of the age-matched controls(indicating increased "total" sympathetic activity). The level of NA in left ventricular tissue of CH model rats was however lower than the age-matched controls. Berberine and captopril showed significant effect on inhibiting the development of cardiac hypertrophy. Berberine decreased plasma NA level and the AD level both in plasma and left ventricular tissue, but had no effect on improving the cardiac NA depletion. Captopril showed significant effect on increasing the depleted cardiac NA and in reducing the elevated plasma NA level. These findings show the efficacy of berberine on modulating the sympathetic nervous activity of rats with experimental cardiac hypertrophy, and reflect the therapeutic potentials of berberine in patients with cardiac hypertrophy and chronic heart failure.

Animals↗
PubMed2001

Evidence for the action potential mediating the changes to contraction observed in cardiac hypertrophy in the rabbit.

BACKGROUND: We investigated the effects of cardiac hypertrophy on intracellular calcium (Ca(2+)) homeostasis, the amounts of proteins involved in calcium regulation and the influence of the action potential on such changes. METHODS: Cardiac hypertrophy was induced in rabbits by constriction of the ascending aorta. They were kept for 6 weeks then the heart was removed and left ventricular myocytes isolated. A portion of these myocytes was immediately frozen and stored for subsequent protein analyses using Western blotting. RESULTS: After aortic banding, cardiac myocyte two-dimensional area and membrane capacitance were increased by 53% and 23% respectively. Hypertrophy prolonged cell contraction and relaxation and the corresponding Indo-1 Ca(2+) transients. Hypertrophied cells displayed longer action potentials but Ca(2+) current densities were unchanged compared with myocytes from sham hearts. If Ca(2+) was released from the sarcoplasmic reticulum using rapid cooling, so bypassing the normal mechanisms involved in excitation-contraction coupling, then no functional differences between hypertrophied and control cells could be observed. Western blot analysis showed that the amounts of sarcoplasmic reticulum Ca(2+) ATPase, its regulatory protein phospholamban and the sodium/calcium exchanger were unchanged whereas the amount of calsequestrin was increased by 65% and the alpha(1) subunit of the sodium/potassium ATPase was reduced by 72%. These changes do not appear to evoke functional consequences under these conditions. CONCLUSION: In this model of cardiac hypertrophy, the increase in action potential duration is responsible for changes in contraction and relaxation.

Action Potentials↗
PubMed2001

Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors.

OBJECTIVES: Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type alpha1B adrenergic receptor (AR) (Tg alpha43), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF). BACKGROUND: Increased myocardial expression of betaARK1 has been shown to be associated with HF and certain models of hypertrophy. METHODS: Tg alpha43 mice and their nontransgenic littermate controls were treated with the alpha1AR agonist phenylephrine (PE) for 3, 7 or 14 days to characterize the cardiac consequences. RESULTS: Nontransgenic littermate control mice treated for 14 days with PE display cardiac hypertrophy with no increase in betaARK1 expression. However, Tg alpha43 animals show a reduced tolerance to 14-day PE treatment, demonstrated by reduced survival and severe cardiac hypertrophy. Moreover, PE treatment for three and seven days in Tg alpha43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced betaAR density and enhanced betaARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y. CONCLUSIONS: These data suggest that PE-treated Tg alpha43 mice have chronic activation of the cardiac sympathetic nervous system, which may be responsible for the appearance of apparent maladaptive hypertrophy with an evolution towards HF and sudden death. Thus, the cardiac phenotypes found in these mice are not the direct result of enhanced alpha1B AR signaling and suggest that betaARK1 is a key molecule in the transition of myocardial hypertrophy to HF.

Adrenergic alpha-Agonists↗
PubMed2001

Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy.

OBJECTIVES: We sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways. BACKGROUND: Cardiac hypertrophy is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Although considerable evidence suggests that G-protein-coupled receptors are involved in the hypertrophic response, it remains controversial whether catecholamines are required for the development of in vivo cardiac hypertrophy. METHODS: We performed transverse aortic constriction (TAC) in dopamine beta-hydroxylase knockout mice (Dbh(-/-), genetically altered mice that are completely devoid of endogenous norepinephrine and epinephrine) and littermate control mice. After induction of cardiac hypertrophy, the mitogen-activated protein kinase (MAPK) signaling pathways were measured in pressure-overloaded/wild-type and Dbh(-/-) hearts. RESULTS: Compared with the control animals, cardiac hypertrophy was significantly blunted in Dbh(-/-) mice, which was not associated with altered cardiac function, as assessed by transthoracic echocardiography in conscious mice. The extracellularly regulated kinase (ERK 1/2), c-jun-NH(2)-terminal kinase (JNK) and p38 MAPK pathways were all activated by two- to threefold after TAC in the control animals. In contrast, induction of the three pathways (ERK 1/2, JNK and p38) was completely abolished in Dbh(-/-) mice. CONCLUSIONS: These data demonstrate a nearly complete requirement of endogenous norepinephrine and epinephrine for the induction of in vivo pressure-overload cardiac hypertrophy and for the activation of hypertrophic signaling pathways.

Animals↗
PubMed1983

Accuracy of echocardiography versus electrocardiography in detecting left ventricular hypertrophy: comparison with postmortem mass measurements.

The accuracy of electrocardiography, M-mode echocardiography and two-dimensional echocardiography in predicting left ventricular hypertrophy was compared in 50 patients who came to autopsy within 6 months after the studies were performed. Several methods for determining left ventricular hypertrophy were examined for each of the three techniques. M-mode echocardiography was technically adequate to evaluate the presence or absence of left ventricular hypertrophy more often than either electrocardiography or two-dimensional echocardiography. Measurements from M-mode echocardiography also correlated best with autopsy measurements. Both echocardiographic techniques had a higher sensitivity than electrocardiographic criteria in diagnosing left ventricular hypertrophy. Two-dimensional echocardiography was not shown to improve the M-mode assessment of left ventricular hypertrophy. In an attempt to simplify both M-mode left ventricular mass calculations and the diagnosis of left ventricular hypertrophy for the clinician, a left ventricular mass nomogram was constructed, enabling quick insertion of standard M-mode echocardiographic measurements.

Adult↗
PubMed1985

Left ventricular diastolic function in elite athletes with physiologic cardiac hypertrophy.

Left ventricular hypertrophy due to aortic stenosis, hypertension and other forms of heart disease is associated with abnormalities of diastolic function. It is uncertain whether these changes are an inherent consequence of the hypertrophic process or represent additional pathologic factors. To investigate this issue, echocardiographic indexes of left ventricular early diastolic function in highly trained athletes were compared with those in age-matched normal control subjects. Athletes were equally classified into two groups: 11 swimmers who had a pattern of myocardial hypertrophy with normal wall thickness to dimension ratio and 11 power lifters whose wall thickness to dimension ratio was increased. The peak rates of left ventricular dimension increase and wall thinning in swimmers and power lifters were greater than in control subjects despite significantly higher left ventricular wall thickness and left ventricular mass index in the athletes. This increase in diastolic function indexes was associated with greater ventricular size and systolic performance. Normalization of the peak rate of dimension increase for end-diastolic dimension and adjustment of the peak rate of wall thinning for the fractional systolic thickening resolved any differences between groups. Thus, after the effects of ventricular size and systolic function were taken into consideration, diastolic function was normal in these subjects with considerable physiologic hypertrophy. This is in contrast to the findings in patients with hypertrophy associated with left ventricular pressure or volume overload, and suggests that abnormalities of diastolic function seen in pathologic hypertrophy are due to factors other than cardiac hypertrophy itself.

Adolescent↗
PubMed1985

Electrocardiographic detection of left ventricular hypertrophy: development and prospective validation of improved criteria.

To develop improved electrocardiographic criteria of left ventricular hypertrophy, individual electrocardiographic voltage measurements were compared with echocardiographic left ventricular mass in a "learning series" of 414 subjects. The strongest independent relations with left ventricular mass were exhibited by the S wave in lead V3, the R wave in lead a VL and the T wave in lead V1 (each p less than 0.001), and by age and sex. Better electrocardiographic detection of left ventricular hypertrophy was achieved by new criteria that stratified QRS voltage and repolarization findings in sex and age subsets. For men, at all ages, left ventricular hypertrophy is suggested by QRS voltage alone when the R wave in lead aVL and the S wave in lead V3 total more than 35 mm. When this voltage exceeds 22 mm, left ventricular hypertrophy is suggested in men under age 40 years when the T wave in lead V1 is positive (greater than or equal to 0 mm), and in men 40 years or older when the T wave in lead V1 is at least 2 mm. For women, at all ages, left ventricular hypertrophy is suggested when the R wave in lead a VL and the S wave in lead V3 total more than 25 mm. When this voltage exceeds 12 mm, left ventricular hypertrophy is suggested in women under 40 when the T wave in lead V1 is positive (greater than or equal to 0 mm), and in women over 40 when the T wave in lead V1 is 2 mm or greater.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1998

Effect of myocardial hypertrophy on systolic and diastolic function in children: insights from the force-frequency and relaxation-frequency relationships.

OBJECTIVE: The objective of this study was to evaluate the effect of myocardial hypertrophy on systolic and diastolic properties of the left ventricle in children. BACKGROUND: In children with myocardial hypertrophy, ejection phase indices are invariably increased. However, indices of force-generation, e.g., end-systolic elastance and invasive indices of diastolic properties, have been studied infrequently in children with myocardial hypertrophy. METHODS: We studied 10 children with congenital aortic stenosis or coarctation of aorta and nine control patients. Systolic properties were assessed from shortening fraction, end-systolic fiber elastance (Ef(es)) measured at resting heart rates, and force-frequency relationship measured at heart rates increasing from 110 to 160 beats per minute. Diastolic properties were assessed from time constant of relaxation (tau) at matched heart rates, chamber stiffness constant, myocardial stiffness constant, and relaxation-frequency relationship measured at gradually increasing heart rates. RESULTS: Ef(es) remained unchanged by myocardial hypertrophy, however, tau was prolonged (tauL: 27.3+/-2.3 vs. 21.8+/-2.2 ms, p < 0.001; and tauD: 43.2+/-3.1 vs. 34.3+/-3.3 ms, p < 0.001). Both chamber and myocardial stiffness constants remained unchanged. Incremental increases in heart rate produced incremental improvement in both contraction and relaxation. Slopes of force-frequency and relaxation-frequency relationships remained unchanged in the experimental group. However, the relaxation-frequency relationship manifested a parallel shift upward. CONCLUSIONS: In conscious, sedated children with myocardial hypertrophy, systolic function assessed by an index of force generation remains unchanged. However, relaxation is prolonged but passive diastolic properties remain unaffected. The combined effect of hypertrophy and heart rate does not alter the force-frequency and relaxation-frequency relationships.

Aortic Coarctation↗
PubMed2005

Extracts enriched in different polyphenolic families normalize increased cardiac NADPH oxidase expression while having differential effects on insulin resistance, hypertension, and cardiac hypertrophy in high-fructose-fed rats.

Insulin resistance and oxidative stress act synergistically in the development of cardiovascular complications. The present study compared the efficacy of three polyphenolic extracts in their capacity to prevent hypertension, cardiac hypertrophy, increased production of reactive oxygen species (ROS) by the aorta or the heart, and increased expression of cardiac NAD(P)H oxidase in a model of insulin resistance. Rats were fed a 60%-enriched fructose food and were treated once a day (gavage) for 6 weeks with 10 mL/kg of water only (F group) or the same amount of solution containing a red grape skin polyphenolic extract enriched in anthocyanins (ANT), a grape seed extract enriched in procyanidins and rich in galloylated procyanidins (PRO), or the commercial preparation Vitaflavan (VIT), rich in catechin oligomers. All treatments were administered at the same dose of 21 mg/kg of polyphenols. Our data indicate that (a) the ANT treatment prevented hypertension, cardiac hypertrophy, and production of ROS, (b) the PRO treatment prevented insulin resistance, hypertriglyceridemia, and overproduction of ROS but had only minor effects on hypertension or hypertrophy, while (c) Vitaflavan prevented hypertension, cardiac hypertrophy, and overproduction of ROS. All polyphenolic treatments prevented the increased expression of the p91phox NADPH oxidase subunit. In summary, our study suggest that (a) the pathogeny of cardiac hypertrophy in the fructose-fed rat disease involves both hypertension and hyperproduction of ROS, (b) polyphenolic extracts enriched in different types of polyphenols possess differential effects on insulin resistance, hypertension, and cardiac hypertrophy, and (c) polyphenols modulate the expression of NAD(P)H oxidase.

Animals↗
PubMed2000

Dexamethasone induced cardiac hypertrophy in newborn rats is accompanied by changes in myosin heavy chain phenotype and gene transcription.

Cardiac hypertrophy has been observed in newborn infants treated with dexamethasone (DEX). This study was undertaken to examine whether DEX-induced hypertrophy in newborn rats is associated with redistribution of cardiac myosin heavy chain (MHC) isoforms and, if so, the effects involve transcriptional regulation. Newborn rats were injected with either DEX (1 mg/kg/day; s.c.) or equivalent volume normal saline for 1, 3, 5, 7 or 9 days. Hypertrophy was quantified by heart dry/wet wt ratios, heart/body wt ratios, and total protein content of the myocardium. Changes in the expression of cardiac MHC mRNA were characterized by northern blot and slot blot analyses, using isoform specific probes for alpha- and beta-MHC genes. DEX effect on alpha-MHC gene transcription was analyzed by transiently transfecting various alpha-MHC promoter/CAT reporter constructs into primary cultures of cardiac myocytes derived from one day old rat pups. DEX administration into newborn rats produced significant cardiac hypertrophy ranging from 23% at day 1 to 59% at 9 days. The hypertrophy was accompanied by immediate increase (83%) in steady state level of the alpha-MHC mRNA within one day and a maximum increase (148%) at 7 days of treatment. The steady state level of beta-MHC mRNA declined by 25% at day 1 and a maximum decrease of 54% at day 7 of DEX treatment. The changes in MHC mRNA were also reflected in their protein levels as determined by V1 and V3 isozyme analysis. DEX treatment of primary cultures of cardiomyocytes following transfection with alpha-MHC promoter/CAT reporter constructs resulted in increased CAT expression in a dose dependent manner. The minimum alpha-MHC gene sequences responding to DEX treatment were located between the -200 to -74-bp region of the gene, resulting in 2-fold and 6-fold activation of CAT reporter after 0.05 and 0.1 mM doses of DEX, respectively. Our data indicate that DEX induced cardiac hypertrophy in newborn rats is accompanied by increased expression of alpha-MHC and decreased expression of beta-MHC. The alpha-MHC effects are mediated in part through transcriptional mechanisms.

Animals↗
PubMed2001

Expression of Ca2+/calmodulin-dependent protein kinase II delta-subunit isoforms in rats with hypertensive cardiac hypertrophy.

Myocardial hypertrophy is characterized by abnormal intracellular Ca2+ handling and decreased contractile performance. Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates numerous Ca2+ handling proteins and thus can regulate intracellular Ca2+ homeostasis directly. We therefore investigated whether differential expression of CaMKII isoforms occurs with cardiac hypertrophy which might promote an abnormal intracellular Ca2+ homeostasis. We further investigated the potential influence of angiotensin (Ang) II on CaMKII expression levels. Hearts from adult Spontaneously Hypertensive Rats (SHR) and hearts from two transgenic rat models with Ang II-dependent hypertension were studied. The expression of the cardiac CaMKII isoforms delta2, delta3, delta4 and delta9 was determined by RT-PCR and immunoblot methods. Rats transgenic for the mouse Ren-2 gene (mrTGR), SHR and controls were studied at the age of 6 months and rats transgenic for the human renin-angiotensin system (hrTGR) from postnatal day 1 to week 8. SHR and mrTGR had an increased heart/body weight ratio (26 and 25%) compared with controls (p < 0.05). SHR hearts showed significantly increased mRNA levels of delta4 and delta9 (p < 0.05) with no change for delta2 and delta3. mrTGR hearts had a significantly increased delta4 and a significantly decreased delta3 transcript level (p < 0.05) with no change for delta2 and delta9. hrTGR hearts developed severe hypertrophy (42%) after postnatal day 14. The neonatal delta2, delta3 and delta4 isoform expression levels were higher (30-100%) compared with SD controls. The levels decreased with increasing age and equalized to controls at week 8, except for delta4 which started to increase after week 4 (p < 0.05). CaMKIIdelta protein levels of all cardiac hypertrophy models were increased in sarcoplasmic reticulum preparations (50-120%) compared with controls (p < 0.05) while the cytosolic levels remained unchanged. Thus, CaMKIIdelta isoforms are differentially expressed in cardiac hypertrophy. The fetal delta4 isoform was constantly expressed. CaMKIIdelta adopts the fetal phenotype independent of the type of hypertrophic stimulus. The observed alterations of CaMKIIdelta isoform patterns may affect intracellular Ca2+ homeostasis and thus contribute to the abnormal contractile phenotype of cardiac hypertrophy.

Age Factors↗
PubMed2001

Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways.

Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent because of its ability to promote hypertrophy. However, the signalling pathways by which IGF-1 promotes hypertrophy remain unclear, with roles suggested for both the calcineurin/NFAT (nuclear factor of activated T cells) pathway and the PtdIns-3-OH kinase (PI(3)K)/Akt pathway. Here we employ a battery of approaches to examine these pathways during the hypertrophic response of cultured myotubes to IGF-1. We report that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrophy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.

3',5'-Cyclic-GMP Phosphodiesterases↗