Letter by Ferté, et al. Regarding Article, "Chronic Pressure Overload Induces Cardiac Hypertrophy and Fibrosis via Increases in SGLT1 and IL-18 Gene Expression in Mice"

The aim of this study was to identify the key genes involved in the cardiac hypertrophy (CH) induced by pressure overload. mRNA microarray data sets GSE5500 and GSE18801 were downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were screened using the Limma package; then, functional and pathway enrichment analysis were performed for common DEGs using the Database for Annotation, Visualization and Integrated Discovery database. Furthermore, the top DEGs were further validated using quantitative PCR in the hypertrophic heart tissue induced by isoprenaline. A total of 113 common DEGs with absolute fold change > 0.5, including 60 significantly upregulated DEGs and 53 downregulated DEGs, were obtained. Gene ontology term enrichment analysis suggested that common upregulated DEG were mainly enriched in neutrophil chemotaxis, extracellular fibril organization, and cell proliferation; and the common downregulated genes were significantly enriched in ion transport, endoplasmic reticulum, and dendritic spine. Kyoto Encyclopedia of Genes and Genomes pathway analysis found that the common DEGs were mainly enriched in extracellular matrix receptor interaction, phagosome, and focal adhesion. Additionally, the expression of Mfap4, Ltbp2, Aspn, Serpina3n, and Cnksr1 were upregulated in the model of CH, while the expression of Anp32a was downregulated. The current study identified the key deregulated genes and pathways involved in the CH, which could shed new light to understand the mechanism of CH.

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P1614Soluble guanylate cyclase as a therapeutic target in heart failure: myocardial gene expression in response to sGC stimulation in pressure overload

European Heart Journal ◽

10.1093/eurheartj/ehz748.0373 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

J Ruedebusch ◽

A Benkner ◽

N Nath ◽

L Kaderali ◽

K Klingel ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Cardiac Hypertrophy ◽

Expression Pattern ◽

Heart Function ◽

Gene Expression Pattern ◽

Pressure Overload ◽

Left Ventricular ◽

Marker Genes ◽

Cgmp Pathway

Abstract Background Heart Failure (HF) is associated with endothelial dysfunction and reduced bioavailability of NO with insufficient stimulation of sGC and reduced production of cGMP. Therefore, the impairment of the NO-sGC-cGMP pathway results in vasoconstriction, platelet aggregation, inflammation, fibrosis and most importantly maladaptive cardiac hypertrophy. The restoration of the NO-sGC -cGMP pathway is an attractive pharmacological target for HF therapy. Purpose Riociguat is an NO independent stimulator of the sGC that sensitizes the sGC to endogenous NO and directly stimulates sGC to produce cGMP. We therefore hypothesized that Riociguat prevents pathological effects occurring during HF. Methods Pressure overload was induced by transverse aortic constriction (TAC) in 8 weeks old male C57Bl6/N mice. Three weeks after TAC when cardiac hypertrophy has developed either Riociguat (RIO; 3 mg/kg) or a Solvent was administered daily for 5 more weeks (n=12 per group). Animals with sham surgery and same drug regime served as controls. The heart function in all groups was evaluated weekly by small animal echocardiography. Eight weeks after surgery, the transcriptome of the left ventricles (LV) of sham and TAC mice were analysed by RNA Sequencing. Differentially expressed genes (DEG) were categorised using Ingenuity Pathway Analysis (IPA). Results TAC resulted in a steady decrease of left ventricular fractional shortening (FS) in the mice until week 3. When Riociguat treatment commenced, the systolic LV function of the TAC+Rio group recovered significantly whereas the solvent group showed a further decline until week 8 (FS 21.4±3.4% vs. 9.5±2%, p<0.001). Both sham groups (Sham+Sol and Sham+Rio) showed no changes in the heart function over timer. Regarding the hypertrophic response to LV pressure overload, Riociguat treatment attenuated significantly the increase of the left ventricular mass (LVM 208.3±15.8mg vs. 148.9±11.8mg, p<0.001) after TAC. In line with the reduced LVM, histological staining showed a significantly reduced fibrosis and myocyte cross sectional area in the TAC+Rio group compared to TAC+Sol group. Regarding the myocardial transcriptome, the treatment with Riociguat resulted in less changes of gene expression pattern after TAC (TAC+Sol vs. Sham+Sol 3160 DEG; TAC+Rio vs. Sham+Rio 2237 DEG). The expression of heart failure marker genes like ANP (Nppa), BNP (Nppb), β-Myosin Heavy Chain (Myh7) and the Collagens 1 and 3 (Col1a1, Col1a2, Col3a1) were significantly decreased in TAC+Rio, when compared to TAC+Sol. IPA analysis revealed that the activation of biological pathways in response to TAC, like actin cytoskeleton- and Integrin signalling, renin-angiotensin or cardiac hypertrophy signalling was attenuated when Riociguat was administered. Conclusion Riociguat attenuates pressure overload induced LV remodelling resulting in less hypertrophy, improved heart function and less alteration of gene expression pattern.

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Abstract 355: Post-translational Modification of Histone Variants in Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.115.suppl_1.355 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Mickey Miller ◽

Aman Makaju ◽

Li Wang ◽

Sarah Franklin

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

Differential Expression Analysis ◽

Pressure Overload ◽

Histone Variants ◽

Neonatal Rat ◽

Global Changes ◽

Label Free ◽

Post Translational Modification ◽

Post Translational Modifications

While global changes in gene expression are a hallmark of cardiac hypertrophy, much less is known regarding the epigenetic factors driving these changes. Local chromatin packing and gene accessibility, which governs transcriptional status, has been correlated with specific post-translational modifications on the histone tails of nucleosomes occupying these regions. However, the specific alterations in histone post-translational modifications driving gene expression changes during cardiac hypertrophy are largely unknown. To identify myocyte specific changes in histone post-translational modifications during cardiac hypertrophy we performed label-free quantitation of nuclear proteins from isolated neonatal rat ventricular myocytes exposed to the hypertrophic agonists, phenylephrine and isoproterenol. Peptide samples were analyzed on a Thermo Orbitrap Velos Pro mass spectrometer using CID & HCD fragmentation. Differential expression analysis was performed using the Progenesis LC-MS software where modified histone peptides were normalized against total protein expression. We observed multiple known and novel post-translational modifications on each of the four core histones, many of which changed in the setting of hypertrophy. To validate these findings in an animal model we performed the same analysis of histone post-translational modifications from cardiac tissue of mice under basal conditions or after pressure-overload induced hypertrophy. This study provides the first global characterization of myocyte specific changes in histone post-translational modifications in cardiac hypertrophy and highlight basic mechanisms of genomic reprogramming operative in disease.

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Diurnal profiling of neuroendocrine genes in murine heart, and shift in proopiomelanocortin gene expression with pressure-overload cardiac hypertrophy

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0050 ◽

2008 ◽

Vol 41 (3) ◽

pp. 117-124 ◽

Cited By ~ 18

Author(s):

Jennifer A Chalmers ◽

Shuo-Yen J Lin ◽

Tami A Martino ◽

Sara Arab ◽

Peter Liu ◽

...

Keyword(s):

Gene Expression ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Cardiac Hypertrophy ◽

Mrna Expression ◽

Leptin Receptor ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Pressure Overload ◽

Pcr Analysis

Neuroendocrine peptides express biologic activity relevant to the cardiovascular system, including regulating heart rate and blood pressure, though little is known about the mechanisms involved. Here, we investigated neuroendocrine gene expression underlying diurnal physiology of the heart. We first used microarray and RT-PCR analysis and demonstrate the simultaneous expression of neuroendocrine genes in normal murine heart, including POMC, GnRH, neuropeptide Y, leptin receptor, GH-releasing hormone, cocaine- and amphetamine-regulated transcript, proglucagon, and galanin. We examined diurnal gene expression profiles, with cosinar bioinformatics to evaluate statistically significant rhythms. The POMC gene exhibits a day/night, circadian or diurnal, pattern of expression in heart, and we postulated that this may be important to cardiac growth and renewal. POMC diurnal gene rhythmicity is altered in pressure-overload cardiac hypertrophy, when compared with control heart, and levels increased at the dark-to-light transition times. These findings are also consistent with the proposal that neuropeptides mediate adverse remodeling processes, such as occur in pathologic hypertrophy. To investigate cellular responses, we screened three cell lines representing fibroblasts, cardiac myocytes, and vascular smooth muscle cells (NIH3T3, heart line 1, and mouse vascular smooth muscle cell line 1 (Movas-1) respectively). POMC mRNA expression is the most notable in Movas-1 cells and, furthermore, exhibits rhythmicity with culture synchronization. Taken together, these results highlight the diverse neuroendocrine mRNA expression profiles in cardiovasculature, and provide a novel model vascular culture system to research the role these neuropeptides play in organ health, integrity, and disease.

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A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure

Science Signaling ◽

10.1126/scisignal.abb5968 ◽

2021 ◽

Vol 14 (676) ◽

pp. eabb5968

Author(s):

Ryan C. Coleman ◽

Akito Eguchi ◽

Melissa Lieu ◽

Rajika Roy ◽

Eric W. Barr ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Cardiac Hypertrophy ◽

G Protein ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Pressure Overload ◽

Nuclear Accumulation ◽

Nuclear Targeting ◽

Amino Terminal

Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers maladaptation and heart failure, in part through the activation of G protein–coupled receptor kinase 5 (GRK5). Hypertrophic stimuli induce the accumulation of GRK5 in the nuclei of cardiomyocytes, where it regulates pathological gene expression through multiple transcription factors including NFAT. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that binds to calmodulin (CaM). Here, we sought to prevent GRK5-mediated pathology in pressure-overload maladaptation and heart failure by expressing in cardiomyocytes a peptide encoding the GRK5 NT (GRK5nt) that encompasses the CaM binding domain. In cultured cardiomyocytes, GRK5nt expression abrogated Gq-coupled receptor–mediated hypertrophy, including attenuation of pathological gene expression and the transcriptional activity of NFAT and NF-κB. We confirmed that GRK5nt bound to and blocked Ca2+-CaM from associating with endogenous GRK5, thereby preventing GRK5 nuclear accumulation after pressure overload. We generated mice that expressed GRKnt in a cardiac-specific fashion (TgGRK5nt mice), which exhibited reduced cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis after chronic transverse aortic constriction. Together, our data support a role for GRK5nt as an inhibitor of pathological GRK5 signaling that prevents heart failure.

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Cardiac Natriuretic Peptide Profiles in Chronic Hypertension by Single or Sequentially Combined Renovascular and DOCA-Salt Treatments

Frontiers in Physiology ◽

10.3389/fphys.2021.651246 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carolina S. Cerrudo ◽

Susana Cavallero ◽

Martín Rodríguez Fermepín ◽

Germán E. González ◽

Martín Donato ◽

...

Keyword(s):

Gene Expression ◽

Left Ventricular Hypertrophy ◽

Cardiac Hypertrophy ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Volume Overload ◽

Left Ventricular ◽

Prolonged Treatment ◽

Chronic Hypertension ◽

Peptide Profiles

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

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Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00612.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. H1635-H1641 ◽

Cited By ~ 16

Author(s):

Tue E. H. Christoffersen ◽

Mark Aplin ◽

Claes C. Strom ◽

Soren P. Sheikh ◽

Ole Skott ◽

...

Keyword(s):

Gene Expression ◽

Left Ventricle ◽

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Pressure Overload ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Natriuretic Peptide Receptor ◽

Angiotensin System ◽

Peptide Receptor

Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg·kg−1·day−1) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% ( P < 0.001) and 520% ( P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.

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Induction of S100β in Myocardium: An Intrinsic Inhibitor of Cardiac Hypertrophy

Canadian Journal of Applied Physiology ◽

10.1139/h98-022 ◽

1998 ◽

Vol 23 (4) ◽

pp. 377-389 ◽

Cited By ~ 12

Author(s):

Thomas G. Parker ◽

James N. Tsoporis

Keyword(s):

Gene Expression ◽

Myocardial Infarction ◽

Cardiac Hypertrophy ◽

Calcium Binding ◽

Cardiac Myocyte ◽

Human Subjects ◽

S100 Protein ◽

Pressure Overload ◽

Cellular Growth ◽

Neonatal Rat

Cardiac hypertrophy induced by pressure overload and following myocardial infarction entails regulation of myocardial gene expression, recapitulating an embryonic phenotype, including activation of fetal β-myosin heavy chain and skeletal α-actin. Progressive hypertrophy and alterations in gene expression may contribute to myocardial failure. Although signaling pathways that contribute to hypertrophy development have been identified, intrinsic cardiac regulators that limit hypertrophic response have not been determined. The β subunit of S100 protein is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced S100β expression in neonatal rat cardiac myocyte cultures and high level expression of S100β in transgenic mice hearts inhibit cardiac hypertrophy and the associated phenotype by modulating protein kinase C-dependent pathways. S100β expression is probably a component of the myocyte response to trophic stimulation that serves as a negative feedback mechanism to limit cellular growth and the associated alterations in gene expression. Key words: gene expression, cardiac myocytes, growth factors, heart failure, calcium-binding proteins

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