scholarly journals Translating Translation to Mechanisms of Cardiac Hypertrophy

2020 ◽  
Vol 7 (1) ◽  
pp. 9 ◽  
Author(s):  
Michael J. Zeitz ◽  
James W. Smyth
Keyword(s):  
Heart Failure ◽  
Protein Synthesis ◽  
Heart Disease ◽  
Cardiac Hypertrophy ◽  
Translational Regulation ◽  
Molecular Mechanisms ◽  
Clinical Investigation ◽  
Translational Machinery ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy

Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation.

scholarly journals Novel genomic targets of valosin-containing protein in protecting pathological cardiac hypertrophy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ning Zhou ◽  
Xin Chen ◽  
Jing Xi ◽  
Ben Ma ◽  
Christiana Leimena ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Bioinformatic Analysis ◽  
Pathological Cardiac Hypertrophy ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Survival Signaling ◽  
G Protein Coupled

Abstract Pressure overload-induced cardiac hypertrophy, such as that caused by hypertension, is a key risk factor for heart failure. However, the underlying molecular mechanisms remain largely unknown. We previously reported that the valosin-containing protein (VCP), an ATPase-associated protein newly identified in the heart, acts as a significant mediator of cardiac protection against pressure overload-induced pathological cardiac hypertrophy. Still, the underlying molecular basis for the protection is unclear. This study used a cardiac-specific VCP transgenic mouse model to understand the transcriptomic alterations induced by VCP under the cardiac stress caused by pressure overload. Using RNA sequencing and comprehensive bioinformatic analysis, we found that overexpression of the VCP in the heart was able to normalize the pressure overload-stimulated hypertrophic signals by activating G protein-coupled receptors, particularly, the olfactory receptor family, and inhibiting the transcription factor controlling cell proliferation and differentiation. Moreover, VCP overexpression restored pro-survival signaling through regulating alternative splicing alterations of mitochondrial genes. Together, our study revealed a novel molecular regulation mediated by VCP under pressure overload that may bring new insight into the mechanisms involved in protecting against hypertensive heart failure.

Abstract 16205: MKP-5 Deficiency Attenuates Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kisuk Min ◽  
Yan Huang ◽  
Frank J Giordano ◽  
Sudip Bajpeyi ◽  
Anton M Bennett
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Muscle ◽  
Molecular Mechanisms ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Body Weight Ratio ◽  
Pathological Cardiac Hypertrophy

Introduction: Cardiac remodeling occurs in response to pathological stimuli including chronic pressure overload, subsequently leading to heart failure. Despite considerable research efforts, the molecular mechanisms responsible for heart failure have yet to be fully elucidated. One of the prominent signaling pathways involved in the development of pathological cardiac hypertrophy is the mitogen-activated protein kinases (MAPKs) pathways. The MAPKs are inactivated by the MAPK phosphatases (MKPs) through direct dephosphorylation. Growing evidence suggests the importance of MKP-5 signaling mechanisms in physiological and pathological processes. However, the role of MKP-5 has not been explored in cardiac muscle. The objective of this study is to investigate how MKP-5-mediated MAPK activity contributes to mechanisms responsible for pressure overload-induced cardiac hypertrophy. Hypothesis: We tested the hypothesis that MKP-5 serves as a central regulator of MAPKs in pressure overload-induced cardiac hypertrophy. Methods: To investigate the role of MKP-5 in cardiac muscle, we caused pressure overload-induced cardiac hypertrophy in wild type (mkp-5 +/+ ) mice and MKP-5 deficient mice (mkp-5 -/- ) through transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiographic analysis at 4 weeks after TAC. Cardiac hypertrophy was measured by heart-to-body weight ratio. Interstitial myocardial fibrosis was evaluated by Sirius red stains and expression of fibrogenic genes was determined by quantitative PCR. Results: Echocardiographic analysis showed that the ejection fraction and fractional shortening of mkp-5 +/+ mice significantly decreased by at 4 weeks after TAC. Heart-to-body weight ratio increased in mkp-5 +/+ mice. However, MKP-5-deficient heart was protected from cardiac dysfunction and cardiac hypertrophy induced by TAC. Importantly, the fibrogenic genes were markedly reduced in mkp-5 -/- mice as compared with mkp-5 +/+ mice at 4 weeks after TAC. Conclusions: Collectively, our study demonstrates that MKP-5 deficiency prevents the heart from pressure overload-induced cardiac hypertrophy and suggests that MKP-5 may serve as a novel therapeutic target for treatment of heart disease.

Abstract 206: A New MicroRNA Family Regulating Cardiac Autophagy and Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Thomas Thum ◽  
Shashi K Gupta ◽  
Ahmet Ucar ◽  
Jan Fiedler ◽  
Leon DeWindt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Hypertrophy ◽  
Cardiac Failure ◽  
Pressure Overload ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy ◽  
Microrna Family ◽  
Causes Of Mortality ◽  
Necessary And Sufficient

Pathologic growth of cardiomyocytes and derailed autophagy are major determinants for the development of heart failure, one of the leading medical causes of mortality worldwide. Here, we show the microRNA (miRNA)-212/132 family to regulate hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli lead to the upregulation of miR-212 and miR-132 expression in cardiomyocytes, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and lethality in mice. Mechanistically, both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and impaired autophagic response upon starvation. Pharmacologic miRNA inhibition by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

Expression of an active LKB1 complex in cardiac myocytes results in decreased protein synthesis associated with phenylephrine-induced hypertrophy

2007 ◽  
Vol 292 (3) ◽  
pp. H1460-H1469 ◽  
Author(s):  
Anna A. Noga ◽  
Carrie-Lynn M. Soltys ◽  
Amy J. Barr ◽  
Suzanne Kovacic ◽  
Gary D. Lopaschuk ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Adaptor Protein ◽  
Neonatal Rat ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy ◽  
Neonatal Rat Cardiac Myocytes ◽  
Rat Cardiac Myocytes

AMP-activated protein kinase (AMPK) is a major metabolic regulator in the cardiac myocyte. Recently, LKB1 was identified as a kinase that regulates AMPK. Using immunoblot analysis, we confirmed high expression of LKB1 in isolated rat cardiac myocytes but show that, under basal conditions, LKB1 is primarily localized to the nucleus, where it is inactive. We examined the role of LKB1 in cardiac myocytes, using adenoviruses that express LKB1, and its binding partners Ste20-related adaptor protein (STRADα) and MO25α. Infection of neonatal rat cardiac myocytes with all three adenoviruses substantially increased LKB1/STRADα/MO25α expression, LKB1 activity, and AMPKα phosphorylation at its activating phosphorylation site (threonine-172). Since activation of AMPK can inhibit hypertrophic growth and since LKB1 is upstream of AMPK, we hypothesized that expression of an active LKB1 complex would also inhibit protein synthesis associated with hypertrophic growth. Expression of the LKB1/STRADα/MO25α complex in neonatal rat cardiac myocytes inhibited the increase in protein synthesis observed in cells treated with phenylephrine (measured via [3H]phenylalanine incorporation). This was associated with a decreased phosphorylation of p70S6 kinase and its substrate S6 ribosomal protein, key regulators of protein synthesis. In addition, we show that the pathological cardiac hypertrophy in transgenic mice with cardiac-specific expression of activated calcineurin is associated with a significant decrease in LKB1 expression. Together, our data show that increased LKB1 activity in the cardiac myocyte can decrease hypertrophy-induced protein synthesis and suggest that LKB1 activation may be a method for the prevention of pathological cardiac hypertrophy.

scholarly journals Flavonoids Extraction from Propolis Attenuates Pathological Cardiac Hypertrophy through PI3K/AKT Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Guang-wei Sun ◽  
Zhi-dong Qiu ◽  
Wei-nan Wang ◽  
Xin Sui ◽  
Dian-jun Sui
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Biological Activities ◽  
Akt Signaling ◽  
Heart Weight ◽  
Pathological Cardiac Hypertrophy ◽  
Wide Range

Propolis, a traditional medicine, has been widely used for a thousand years as an anti-inflammatory and antioxidant drug. The flavonoid fraction is the main active component of propolis, which possesses a wide range of biological activities, including activities related to heart disease. However, the role of the flavonoids extraction from propolis (FP) in heart disease remains unknown. This study shows that FP could attenuate ISO-induced pathological cardiac hypertrophy (PCH) and heart failure in mice. The effect of the two fetal cardiac genes, atrial natriuretic factor (ANF) andβ-myosin heavy chain (β-MHC), on PCH was reversed by FP. Echocardiography analysis revealed cardiac ventricular dilation and contractile dysfunction in ISO-treated mice. This finding is consistent with the increased heart weight and cardiac ANF protein levels, massive replacement fibrosis, and myocardial apoptosis. However, pretreatment of mice with FP could attenuate cardiac dysfunction and hypertrophyin vivo. Furthermore, the cardiac protection of FP was suppressed by the pan-PI3K inhibitor wortmannin. FP is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorder, such as fibrosis. The effects may be closely correlated with PI3K/AKT signaling. FP may be clinically used to inhibit PCH progression and heart failure.

scholarly journals Heart failure—emerging roles for the mitochondrial pyruvate carrier

2021 ◽  
Author(s):  
Mariana Fernandez-Caggiano ◽  
Philip Eaton
Keyword(s):  
Heart Failure ◽  
Warburg Effect ◽  
Translational Regulation ◽  
Hypertrophic Growth ◽  
Metabolic Adaptations ◽  
Mitochondrial Pyruvate Carrier ◽  
Heart Failure Progression ◽  
Mitochondrial Oxidation ◽  
Human And Mouse ◽  
The Warburg Effect

AbstractThe mitochondrial pyruvate carrier (MPC) is the entry point for the glycolytic end-product pyruvate to the mitochondria. MPC activity, which is controlled by its abundance and post-translational regulation, determines whether pyruvate is oxidised in the mitochondria or metabolised in the cytosol. MPC serves as a crucial metabolic branch point that determines the fate of pyruvate in the cell, enabling metabolic adaptations during health, such as exercise, or as a result of disease. Decreased MPC expression in several cancers limits the mitochondrial oxidation of pyruvate and contributes to lactate accumulation in the cytosol, highlighting its role as a contributing, causal mediator of the Warburg effect. Pyruvate is handled similarly in the failing heart where a large proportion of it is reduced to lactate in the cytosol instead of being fully oxidised in the mitochondria. Several recent studies have found that the MPC abundance was also reduced in failing human and mouse hearts that were characterised by maladaptive hypertrophic growth, emulating the anabolic scenario observed in some cancer cells. In this review we discuss the evidence implicating the MPC as an important, perhaps causal, mediator of heart failure progression.

Abstract P320: The Gut Microbial Metabolite Butyrate Suppresses Cardiac Hypertrophy Via An Epigenetic Mechanism

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Masahiko Umei ◽  
Hiroshi Akazawa ◽  
Akiko Saga-Kamo ◽  
Hiroki Yagi ◽  
Qing Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Epigenetic Mechanism ◽  
Neonatal Rat ◽  
Short Chain ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Growth

Introduction: Short-chain fatty acids (SCFA) are one of the gut microbial metabolites that can influence host health and disease. We previously reported that gut dysbiosis is associated with heart failure, and that the proportion of butyrate-producing bacteria is decreased in the gut of patients with heart failure. Purpose: We investigated the molecular mechanism of butyrate in the development of cardiac hypertrophy. Methods and Results: Single-cell transcriptome analysis and co-expression network analysis revealed that G protein-coupled receptors for short-chain fatty acid receptors were not expressed in cardiomyocytes and that Olfr78 was expressed in vascular smooth muscle cells in the heart. On the other hand, treatment with butyrate inhibited ET1-induced and isoproterenol (ISO)-induced hypertrophic growth in cultured neonatal rat cardiomyocytes. Moreover, butyrate increased the acetylation levels of histone H3, suggesting the inhibitory effect of butyrate on HDAC. In addition, butyrate caused the degradation of HDAC2 and up-regulation of Inpp5f, encoding inositol polyphosphate-5-phosphatase f, leading to a significant decrease in the phosphorylation levels of Akt and glycogen synthase kinase 3β (GSK3β). Finally, intraperitoneal injection of butyrate inhibited ISO-induced cardiac hypertrophy in mice. These results suggest that butyrate protects against hypertrophic responses via suppression of the Akt-GSK3β pathway through HDAC inhibition. Conclusion: In the heart, there were no known short-chain fatty acid receptors in cardiomyocytes. However, butyrate was shown to have an epigenetic mechanism in suppressing effect on cardiomyocyte hypertrophy via suppression of HDAC2-Akt-GSK3β axis. Our results uncover a potential link between dysbiosis of intestinal microbiota and the development of cardiac hypertrophy.

HEMANGIOMA OF THE LIVER WITH HEART FAILURE: A CASE REPORT

PEDIATRICS ◽  
1954 ◽  
Vol 14 (2) ◽  
pp. 117-121
Author(s):  
ROBERT W. WINTERS ◽  
SAUL J. ROBINSON ◽  
GEORGE BATES
Keyword(s):  
Heart Failure ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Case Report ◽  
Cardiac Hypertrophy ◽  
Cardiac Failure ◽  
Congenital Heart ◽  
Signs And Symptoms ◽  
Post Mortem ◽  
Great Vessels

A case of multiple hemangiomata of the liver is reported in an infant who presented signs and symptoms strongly suggesting congenital heart disease. The post mortem examination revealed no gross anomalies of the heart or great vessels, but did show a heart with cardiac hypertrophy. A mechanism to explain the cardiac failure in this case is discussed.

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

2018 ◽  
Vol 115 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Andrea Grund ◽  
Malgorzata Szaroszyk ◽  
Janina K Döppner ◽  
Mona Malek Mohammadi ◽  
Badder Kattih ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Binding Protein ◽  
Treatment Strategies ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure

2006 ◽  
Vol 27 (2) ◽  
pp. 156-170 ◽  
Author(s):  
Stephan Schiekofer ◽  
Ichiro Shiojima ◽  
Kaori Sato ◽  
Gennaro Galasso ◽  
Yuichi Oshima ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Expression Profiles ◽  
Active Form ◽  
Heart Tissue ◽  
Compensatory Hypertrophy ◽  
Transcript Expression ◽  
Heart Size

To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, we developed a tetracycline-regulated transgenic system to conditionally switch a constitutively active form of the Akt1 protein kinase on or off in the adult heart. Short-term activation (2 wk) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 wk) induced extensive cardiac hypertrophy, severe contractile dysfunction, and massive interstitial fibrosis. The focus of this study was to create a transcript expression profile of the heart as it undergoes reversible Akt1-mediated hypertrophy and during the transition from compensated hypertrophy to heart failure. Heart tissue was analyzed before transgene induction, 2 wk after transgene induction, 2 wk of transgene induction followed by 2 days of repression, 6 wk after transgene induction, and 6 wk of transgene induction followed by 2 wk of repression. Acute overexpression of Akt1 (2 wk) leads to changes in the expression of 826 transcripts relative to noninduced hearts, whereas chronic induction (6 wk) led to changes in the expression of 1,611, of which 65% represented transcripts that were regulated during the pathological phase of heart growth. Another set of genes identified was uniquely regulated during heart regression but not growth, indicating that nonoverlapping transcription programs participate in the processes of cardiac hypertrophy and atrophy. These data define the gene regulatory programs downstream of Akt that control heart size and contribute to the transition from compensatory hypertrophy to heart failure.

Sign in / Sign up

Export Citation Format

Share Document