Re-expression Of Fetal Genes Research Articles

Conditional Cardiac Overexpression of S100A6 Attenuates Myocyte Hypertrophy and Apoptosis Following Myocardial Infarction

S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the rat heart following infarction and forced expression of S100A6 in rat neonatal cardiac myocyte cultures, inhibited the induction of β myosin heavy chain (MHC), skeletal α actin (skACT) and myocyte apoptosis in response to diverse stimuli including tumor necrosis factor α. To define a role for S100A6 in vivo, we generated cardiac myocyte-specific transgenic mice by placing the human S100A6 cDNA downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA) and breeding this line with one harboring cardiac myocyte-restricted (αMHC) expression of tTA (αMHC-tTA). We compared S100A6-αMHC-tTA mice 35 days post-myocardial infarction (MI) produced by coronary artery ligation with similar matched sham-operated controls on (S100A6 transgene overexpressed) or off (S100A6 transgene silenced) DOX. There were no differences between the sham groups on or off DOX. Thirty five days post-MI, myocardial S100A6 levels increased 12.5-fold in S100A6-α-MHC-tTA mice off DOX compared with S100A6-α-MHC-tTA mice on DOX. Hemodynamic studies, echocardiography and postmortem examination indicated that S100A6-αMHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (20-22.5 % increase) accompanied by a program of fetal gene re-expression, fibrosis and myocardial apoptosis. Whereas the S100A6-α-MHC-tTA mice off DOX showed an attenuated myocyte hypertrophic response, less fibrosis and apoptosis which was beneficial to preservation of cardiac function. Therefore, S100A6 is a potential therapeutic target for modulation of adverse left ventricular remodeling in the early post infarct period.

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

TRPM4 channel re-expression after myocardial infarction is essential for survival in mice

Introduction: TRPM4 is a Ca2+-activated non selective cation channel involved in conduction disorders. TRPM4 is expressed in sinoatrial and atrial cells but only poorly in ventricles. However, in vitro studies detected this current in cardiac hypertrophy concomitantly with fetal gene re-expression. The aim of our study was to investigate whether TRPM4 plays a functional role in ventricular cardiomyocytes in hypertrophy following Myocardial Infarction (MI). Methods: MI was induced by left coronary artery ligation in Trpm4-gene knock-out (Trpm4-/-) and Trpm4+/+ mice (23 and 12, respectively). Post-MI heart failure was verified using Doppler-echocardiography. Electrocardiograms (ECGs) were recorded by telemetry during 12h. Left Ventricular (LV) cardiomyocytes were isolated 4 weeks after MI. Action Potential (AP) and TRPM4-current were recorded using the patch-clamp technique. The propensity of cells to trigger spontaneous electrical activities was assessed. Store-Operated Ca2+-Entry (SOCE), negatively regulated by TRPM4, was measured using fluorescence microscopy. TRPM4 transcript and protein expression in left ventricle were studied using qPCR and western blot analysis. Results: Kaplan-Meier analysis evidenced a higher mortality rate for Trpm4-/–MI mice when compared with Trpm4+/+-MI animals (56% vs. 91%, P=0.03). Echocardiograms showed increased LV mass (3.85±0.4 vs. 2.49±0.2 mg/g, P=0.009) while fractional shortening was reduced (15.2±1.5 vs. 22.7±2.2, P=0.013) in Trpm4-/–MI vs. Trpm4+/+-MI mice. The number of premature ventricular complexes was increased in Trpm4-/–MI vs. Trpm4+/+-MI mice (57±5 vs. 35±3, P=0.028). Surprisingly, there was no difference in the lengthening of AP in LV myocytes following MI between Trpm4-/- and Trpm4+/+ (APD90: 94.4±23 vs. 88±15 ms, P=0.58, respectively). However, Trpm4-/–MI cells exhibited more EADs and DADs than Trpm4+/+-MI (EADs: 11/25 vs. 6/30, P=0.02; DADs: 8/25 vs. 2/30, P=0.008). Moreover, an increase of Trpm4 transcript was found in Trpm4+/+-MI ventricle, associated with TRPM4 protein presence (western blot) and function (TRPM4 current: 1.28±0.1 vs. 0.01±0.06 pA/pF at +40 mV, P=0.001). This expression correlated to a decrease of SOCE in cardiomyocytes from MI group vs. sham group (P=0.001). Conclusion: Lack of TRPM4 channel re-expression in the LV worsened the deleterious effects of post-MI cardiac remodeling on survival, hypertrophy, heart function, and arrhythmic events. Negative regulation of SOCE, involved in cardiac remodeling, and occurrence of spontaneous cellular arrhythmias suggests that TRPM4 channel plays a critical role in post-MI adaptations.

Epigenetics: a new mechanism of regulation of heart failure?

Heart failure is a syndrome resulting from a complex genetic predisposition and multiple environmental factors, and is a leading cause of morbidity and mortality. It is frequently accompanied by changes in heart mass, size, and shape, a process known as pathological cardiac remodeling. At the molecular level, these changes are preceded and accompanied by a specific gene expression program characterized by expression of certain ‘fetal’ genes. This re-expression of fetal genes in the adult heart contributes to the development of the syndrome. Therefore, counteracting the gene expression changes occurring in heart failure could be a therapeutic approach for this pathology. One mechanism of gene expression regulation that has gained importance is epigenetics. This review gives an overview of the roles of some epigenetic mechanisms, such as DNA methylation, histone modifications, ATP-dependent chromatin remodeling, and microRNA-dependent mechanisms, in heart failure.

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Restoration of Cardiac Tissue Thyroid Hormone Status in Experimental Hypothyroidism: A Dose-Response Study in Female Rats

Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T(3) (instead of T(4)) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T(3) dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T(3) and T(4) levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T(3) led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T(3) levels was not associated with restoration of cardiac tissue T(3) levels or cardiac function. In fact, a 3-fold higher T(3) dosage was necessary to normalize cardiac tissue T(3) levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states.

MiR‐221 promotes cardiac hypertrophy in vitro through the modulation of p27 expression

Cardiac hypertrophy has been known as an independent predictor for cardiovascular morbidity and mortality. Molecular mechanisms underlying the development of heart failure remain elusive. Recently, microRNAs (miRs) have been established as important regulators in cardiac hypertrophy. Here, we reported miR-221 was up-regulated in both transverse aortic constricted mice and patients with hypertrophic cardiomyopathy (HCM). Forced expression of miR-221 by transfection of miR-221 mimics increased myocyte cell size and induced the re-expression of fetal genes, which were inhibited by the knockdown of endogenous miR-221 in cardiomyocytes. The TargetScan algorithm-based prediction identified that p27, a cardiac hypertrophic suppressor, is the putative target of miR-221, which was confirmed by luciferase assay and Western blotting. In conclusion, our results demonstrated that miR-221 regulated cardiomyocyte hypertrophy probably through down-regulation of p27, suggesting that miR-221 may be a new intervention target for cardiac hypertrophy.

Terminal Differentiation, Advanced Organotypic Maturation, and Modeling of Hypertrophic Growth in Engineered Heart Tissue

Cardiac tissue engineering should provide "realistic" in vitro heart muscle models and surrogate tissue for myocardial repair. For either application, engineered myocardium should display features of native myocardium, including terminal differentiation, organotypic maturation, and hypertrophic growth. To test the hypothesis that 3D-engineered heart tissue (EHT) culture supports (1) terminal differentiation as well as (2) organotypic assembly and maturation of immature cardiomyocytes, and (3) constitutes a methodological platform to investigate mechanisms underlying hypertrophic growth. We generated EHTs from neonatal rat cardiomyocytes and compared morphological and molecular properties of EHT and native myocardium from fetal, neonatal, and adult rats. We made the following key observations: cardiomyocytes in EHT (1) gained a high level of binucleation in the absence of notable cytokinesis, (2) regained a rod-shape and anisotropic sarcomere organization, (3) demonstrated a fetal-to-adult gene expression pattern, and (4) responded to distinct hypertrophic stimuli with concentric or eccentric hypertrophy and reexpression of fetal genes. The process of terminal differentiation and maturation (culture days 7-12) was preceded by a tissue consolidation phase (culture days 0-7) with substantial cardiomyocyte apoptosis and dynamic extracellular matrix restructuring. This study documents the propensity of immature cardiomyocytes to terminally differentiate and mature in EHT in a remarkably organotypic manner. It moreover provides the rationale for the utility of the EHT technology as a methodological bridge between 2D cell culture and animal models.

β-MyHC and Cardiac Hypertrophy

See related article, pages 629–638 In response to stress signals, the mammalian heart responds by an increase in its size.1 This is largely accomplished by an increase in the size of myocytes (hypertrophy) rather than by increasing their numbers (hyperplasia). At the molecular level, pathological stresses induce multiple changes, including genetic reprogramming—the reexpression of a battery of fetal genes and the downregulation of multiple adult genes.2 Together, the changes in gene expression result in substantial phenotypic changes, including changes in size, contractility, metabolic state, and electric conductance. Indeed, the reexpression of fetal genes, including β-myosin heavy chain (β-MyHC), atrial natriuretic factor (ANF), and alpha-skeletal actin, has for many years been looked on as an important molecular indicator of pathological hypertrophy. In spite of this use of β-MyHC reexpression as a marker of pathological hypertrophy, until recently there have been surprisingly few reports on β-MyHC reexpression at the level of individual myocytes within the hypertrophic heart. Nevertheless, previous work using in situ hybridization against β-MyHC mRNA has shown that reexpression of β-MyHC does not take place in all areas of the hypertrophic heart; rather, it is distributed in distinct regions.3 More recently, it has been possible to study individual cells from the heart using genetically altered mice in which a fluorescent protein (yellow fluorescent protein [YFP]) is tagged onto the native β-MyHC gene. This procedure confirmed that β-MyHC reexpression takes place in cells located in distinct regions, including regions adjacent to areas of …

Nandrolone and resistance training induce heart remodeling: Role of fetal genes and implications for cardiac pathophysiology

AimsThis study was conducted to assess the isolated and combined effects of nandrolone and resistance training on cardiac morphology, function, and mRNA expression of pathological cardiac hypertrophy markers. Main methodsWistar rats were randomly divided into four groups and submitted to 6weeks of treatment with nandrolone and/or resistance training. Cardiac parameters were determined by echocardiography. Heart was analyzed for collagen infiltration. Real-time RT-PCR was used to assess the pathological cardiac hypertrophy markers. Key findingsBoth resistance training and nandrolone induced cardiac hypertrophy. Nandrolone increased the cardiac collagen content, and reduced the cardiac index in non-trained and trained groups, when compared with the respective vehicle-treated groups. Nandrolone reduced the ratio of maximum early to late transmitral flow velocity in non-trained and trained groups, when compared with the respective vehicle-treated groups. Nandrolone reduced the alpha-myosin heavy chain gene expression in both non-trained and trained groups, when compared with the respective vehicle-treated groups. Training reduced the beta-myosin heavy chain gene expression in the groups treated with vehicle and nandrolone. Only the association between training and nandrolone increased the expression of the skeletal alpha-actin gene and atrial natriuretic peptide in the left ventricle. SignificanceThis study indicated that nandrolone, whether associated with resistance training or not, induces cardiac hypertrophy, which is associated with enhanced collagen content, re-expression of fetal genes the in left ventricle, and impaired diastolic and systolic function.

Molecular Pathways Underlying Cardiac Remodeling During Pathophysiological Stimulation

Cardiac remodeling involves molecular, cellular, and interstitial changes that manifest clinically as changes in size, shape, and function of the heart after injury or stress stimulation.1 Although the term cardiac remodeling was initially coined to describe the prominent changes that occur after myocardial infarction,2,3 it is clear that similar processes transpire after other types of injury such as with pressure overload (aortic valve stenosis, hypertension), inflammatory disease (myocarditis), idiopathic dilated cardiomyopathy, and volume overload (valvular regurgitation). Although the causes of these diseases are different, they share molecular, biochemical, and cellular events to collectively change the shape of the myocardium. Cardiac hypertrophy is a common type of cardiac remodeling that occurs when the heart experiences elevated workload. The heart and individual myocytes enlarge as a means of reducing ventricular wall and septal stress when faced with increased workload or injury. Cardiac hypertrophy is classified as “physiological” when it occurs in healthy individuals after exercise or pregnancy and is not associated with cardiac damage. In contrast, hypertrophy that results from pressure or volume overload or after myocardial infarction is usually referred to as “pathological.” This name may be misleading, however, because pathological hypertrophy may also involve a compensatory and adaptive phase that tends to reduce wall stress and maintain output, although ultimately these positive aspects are lost and ventricular function declines, often leading to heart failure. In addition to ventricular remodeling, pathological cardiac hypertrophy involves cellular and molecular remodeling such as myocyte growth without significant proliferation, reexpression of fetal genes, alterations in the expression of proteins involved in excitation-contraction coupling, and changes in the energetic and metabolic state of the myocyte. These cellular and molecular changes within the myocyte are accompanied by changes in the extracellular matrix (ECM) and by myocyte death caused by necrosis or apoptosis. As …

Common MicroRNA Signatures in Cardiac Hypertrophic and Atrophic Remodeling Induced by Changes in Hemodynamic Load

BackgroundMechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy. Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. MicroRNAs (miRNAs) are discussed as superordinate regulators of global gene networks acting mainly at the translational level. Here, we hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses.Methodology/Principal FindingsWe employed ascending aortic stenosis (AS) and heterotopic heart transplantation (HTX) in syngenic Lewis rats to induce mechanical overloading and unloading, respectively. Heart weight was 26±3% higher in AS (n = 7) and 33±2% lower in HTX (n = 7) as compared to sham-operated (n = 6) and healthy controls (n = 7). Small RNAs were enriched from the left ventricles and subjected to quantitative stem-loop specific RT-PCR targeting a panel of 351 miRNAs. In total, 153 miRNAs could be unambiguously detected. Out of 72 miRNAs previously implicated in the cardiovascular system, 40 miRNAs were regulated in AS and/or HTX. Overall, HTX displayed a slightly broader activation pattern for moderately regulated miRNAs. Surprisingly, however, the regulation of individual miRNA expression was strikingly similar in direction and amplitude in AS and HTX with no miRNA being regulated in opposite direction. In contrast, fetal hearts from Lewis rats at embryonic day 18 exhibited an entirely different miRNA expression pattern.ConclusionsTaken together, our findings demonstrate that opposite changes in cardiac workload induce a common miRNA expression pattern which is markedly different from the fetal miRNA expression pattern. The direction of postnatal adaptive cardiac growth does, therefore, not appear to be determined at the level of single miRNAs or a specific set of miRNAs. Moreover, miRNAs themselves are not reprogrammed to a fetal program in response to changes in hemodynamic load.

Going Out on a LIM and Cysteine-Rich Domains 1 Limb

Hypertension induces cardiac myocytes in the left ventricle to activate a hypertrophic response that involves the upregulation of contractile proteins and the re-expression of fetal genes.1 Transcriptional induction is an important component of this response, and the zinc finger-containing transcription factors GATA4 and GATA6 have been shown to directly stimulate cardiac hypertrophy.2 LIM domain proteins (named after the first 3 LIM proteins identified: Lin11, Isl-1, and Mec-3) interact with transcriptional regulators, kinases, and structural proteins. Because of these protein-protein interactions, LIM domain proteins have been assigned roles in cell growth, differentiation, and cytoskeletal remodeling.3 Several LIM proteins have been identified by proteomic and functional screens of left ventricles subjected to pressure overload.4,5 LIM and cysteine-rich domains 1 (Lmcd1) protein has 2 LIM domains in the C-terminus and a cysteine-rich domain in the N-terminus. Because it contains ≥1 LIM domain in the C-terminus, Lmcd1 is classified as a group 3 LIM protein, and most of the previously identified group 3 LIM proteins have been shown to localize to the cytoplasm. Lmcd1 is expressed in most tissues and is particularly highly expressed in cardiac and skeletal muscle.6 Beyond a …

A Translational Approach to Hypertensive Heart Disease

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

H017 Time dependent activation of AKT-GSK3beta and calcineurin signaling pathways during the development of TAC-induced left ventricular hypertrophy in B6D2/F1 mice

Left ventricular hypertrophy (LVH) is an adaptive response to chronic biomechanical stress that later progresses to maladaptive hypertrophy and heart failure. To better understand the mechanisms responsible for LVH development, we studied the activation of two major kinases, protein kinase B (Akt/PKB) and glycogen synthase kinase3b (GSK3b) and of a phosphatase, calcineurin (Cn) in an experimental model of thoracic aorta constriction (TAC). 4 week-old B6D2/F1 male, Sham-operated (Sham) and TAC mice were studied 3, 7, 15, 30 and 60 days post-TAC. Gene expression and activation of signalling pathways was studied by PCR and Western Blot. TAC-induced LVH (10 – 51 % at days 3-60, respectively) was associated with: 1) fetal gene reexpression characterised by an increase in mRNA levels of BNP (1.7-3 fold) and a-SK (2-4 fold), an a- to b-MHC switch seen at day 30 only ; 2) a significant increase in SERCA2a (1.7 fold), PLB, and NCX (3.6 fold) protein levels at day 7. 3) a 2 fold increase in P-Akt at day 3 and a decrease at day 15 while Akt was increased at days 7 and 15 ; 4) an increase in P-GSK3b at day 15 (1.5 fold), whereas no change in Akt and GSK3b protein levels were seen at days 30 and 60 ; 5) a significant decrease in CnAb at day 15 (2 fold). LVH develops progressively from day 3 in response to TAC, accompanied by re-expression of the fetal gene program. The alpha to beta-MHC mRNA switch occurs late, associated with the transition to HF, which occurs progressively with time. At days 3 and 15, P-Akt acts as an upstream regulator of GSK3b which may favour the development of LVH. 7 days post-TAC, a SERCA2a and NCX increase might contribute to decrease free cytosolic calcium level. At day 15, a further increase in LVH is associated with an increase in Cn activity and an increase GSK3b, which may counteract the hypertrophic response. Taken together, our data suggest a time-dependent cross-talk between Cn and GSK3b to modulate cardiac hypertrophic response to pressure overload.

Abstract 1831: Phosphodiesterase-5 Inhibition Prevents Cardiac Hypertrophy, Independently of the Calcineurin Pathway

Cyclic GMP and its downstream kinase protein kinase G (PKG) negatively regulate cardiac hypertrophy. To date the only documented target of this cascade is the serine-threonine phosphatase calcineurin (Cn), whose activation is central to the development of pathologic cardiac hypertrophy. Recently, we reported that phosphodiesterase 5 (PDE5) inhibition (sildenafil, SIL) activates myocardial PKG and prevents pressure-overload induced hypertrophy by suppressing multiple cascades including Cn. To test the centrality of Cn signaling to the in vivo anti-hypertrophic effects of SIL, we subjected mice deficient in the Cn-A β subunit (CnA β −/− ) to severe trans-aortic constriction (TAC) with or without SIL (100mg/kg/day, p.o.) for 3-wks. TAC induced less hypertrophy that was more concentric in CnA β −/− vs WT-controls (50% vs 100% increase in heart mass/tibia length, p&lt;0.03). SIL completely blocked the hypertrophic response and fully normalized fetal gene re-expression (e.g ANP, BNP and β MHC) in CnA β −/− TAC hearts, while it inhibited LVH by 60% and suppressed ANP and β MHC in WT-TAC hearts. SIL improved cardiac systolic and diastolic function (pressure-volume analysis) in CnA β −/− TAC hearts much as in WT-TAC hearts. In CnA β −/− TAC hearts, phosphorylated calcium calmodulin kinase II (CaMK II) increased 10-fold versus only a 2-fold rise in WT-TAC, whereas Akt and glycogen synthase kinase 3 β (GSK3 β ) activation were comparable between groups. Extracellular response kinase (ERK) 1/2 was activated with TAC in WT hearts only. Importantly, SIL stimulated myocardial PKG and markedly inhibited the activation of CaMKII, Akt and GSK3 β similarly in both groups exposed to TAC. Thus, Cn is not required for the anti-hypertrophic effects of SIL. Though TAC-induced hypertrophy is less in CnA β −/− mice, SIL remains effective in suppressing the residual response by targeting alternative cascades such as CaMK II. These findings suggest that SIL acts either on multiple pathways concurrently, or at a node proximal to these pathways likely at or near the sarcolemmal membrane.

PDC deletion: the way to a man's heart disease

the heart has continuous high-energy demands required to sustain efficient contraction. This is met by the metabolism of major circulating substrates (e.g., glucose, lactate, or lipids), according to availability, since the heart has a limited capacity for nutrient storage (reviewed in Ref. [16][1

YY1 Protects Cardiac Myocytes from Pathologic Hypertrophy by Interacting with HDAC5

YY1 is a transcription factor that can repress or activate the transcription of a variety of genes. Here, we show that the function of YY1 as a repressor in cardiac myocytes is tightly dependent on its ability to interact with histone deacetylase 5 (HDAC5). YY1 interacts with HDAC5, and overexpression of YY1 prevents HDAC5 nuclear export in response to hypertrophic stimuli and the increase in cell size and re-expression of fetal genes that accompany pathological cardiac hypertrophy. Knockdown of YY1 results in up-regulation of all genes present during fetal development and increases the cell size of neonatal cardiac myocytes. Moreover, overexpression of a YY1 deletion construct that does not interact with HDAC5 results in transcription activation, suggesting that HDAC5 is necessary for YY1 function as a transcription repressor. In support of this relationship, we show that knockdown of HDAC5 results in transcription activation by YY1. Finally, we show that YY1 interaction with HDAC5 is dependent on the HDAC5 phosphorylation domain and that overexpression of YY1 reduces HDAC5 phosphorylation in response to hypertrophic stimuli. Our results strongly suggest that YY1 functions as an antihypertrophic factor by preventing HDAC5 nuclear export and that up-regulation of YY1 in human heart failure may be a protective mechanism against pathological hypertrophy.

Is cardiac hypertrophy a required compensatory mechanism in pressure-overloaded heart?

Is cardiac hypertrophy a required compensatory mechanism in pressure-overloaded heart?

Gene profiling during regression of pressure overload-induced cardiac hypertrophy

Regression of cardiac hypertrophy and improvement of the functional capacity of failing hearts have reportedly been achieved by mechanical unloading in cardiac work. In this study, cardiac hypertrophy was first induced in rats by transverse aortic constriction and then mechanically unloaded by relieving the constriction after significant cardiac hypertrophy had developed. Hypertrophy was significantly regressed at the cellular and molecular levels at day 1, 3, and 7 after constriction relief. Gene profiling analysis revealed that 52 genes out of 9,911 genes probed on a gene array were specifically upregulated during the early regression period. Among these regression-induced genes, Eyes absent 2 (eya2) was of particular interest because it is a transcriptional cofactor involved in mammalian organogenesis as well as Drosophila eye development. Adenovirus-mediated overexpression of eya2 in rat neonatal cardiomyocytes completely abrogated phenylephrine-induced development of cardiomyocyte hypertrophy as determined by cell size, sarcomere rearrangement and fetal gene re-expression. Our data strongly suggest that transcriptional programs distinct from those mediating cardiac hypertrophy may be operating during the regression of hypertrophy, and eya2 may be a key regulator of one of these programs.