scholarly journals Cardiac gene expression profile in rats with terminal heart failure and cachexia

2005 ◽  
Vol 20 (3) ◽  
pp. 256-267 ◽  
Author(s):  
Maren Wellner ◽  
Ralf Dechend ◽  
Joon-Keun Park ◽  
Erdenechimeg Shagdarsuren ◽  
Nidal Al-Saadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Expression Profile ◽  
Left Ventricular ◽  
Altered Expression ◽  
Cardiac Gene Expression ◽  
Terminal Heart Failure ◽  
Cardiac Gene ◽  
Blood Pressures

About one-half of double transgenic rats (dTGR) overexpressing the human renin and angiotensinogen genes die by age 7 wk of terminal heart failure (THF); the other (preterminal) one-half develop cardiac damage but survive. Our study’s aim was to elucidate cardiac gene expression differences in dTGR-THF compared with dTGR showing compensated cardiac hypertrophy but not yet THF. dTGR treated with losartan (LOS) and nontransgenic rats (SD) served as controls. THF-dTGR body weight was significantly lower than for all other groups. At death, THF-dTGR had blood pressures of 228 ± 7 mmHg (cardiac hypertrophy index 6.2 ± 0.1 mg/g). Tissue Doppler showed reduced peak early (Ea) to late (Aa) diastolic expansion in THF-dTGR, indicating diastolic function. Preterminal dTGR had blood pressures of 197 ± 5 mmHg (cardiac hypertrophy index 5.1 ± 0.1 mg/g); Ea < Aa compared with LOS-dTGR (141 ± 6 mmHg; 3.7±0.1 mg/g; Ea > Aa) and SD (112 ± 4 mmHg; 3.6 ± 0.1 mg/g; Ea > Aa). Left ventricular RNA was isolated for the Affymetrix system and TaqMan RT-PCR. THF-dTGR and dTGR showed upregulation of hypertrophy markers and α/β-myosin heavy chain switch to the fetal isoform. THF-dTGR (vs. dTGR) showed upregulation of 239 and downregulation of 150 genes. Various genes of mitochodrial respiratory chain and lipid catabolism were reduced. In addition, genes encoding transcription factors (CEBP-β, c-fos, Fra-1), coagulation, remodeling/repair components (HSP70, HSP27, heme oxygenase), immune system (complement components, IL-6), and metabolic pathway were differentially expressed. In contrast, LOS-dTGR and SD had similar expression profiles. These data demonstrate that THF-dTGR show an altered expression profile compared with preterminal dTGR.

Myoglobin-deficient mice activate a distinct cardiac gene expression program in response to isoproterenol-induced hypertrophy

2010 ◽  
Vol 41 (2) ◽  
pp. 137-145 ◽  
Author(s):  
Andrei Molojavyi ◽  
Antje Lindecke ◽  
Annika Raupach ◽  
Sarah Moellendorf ◽  
Karl Köhrer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Gene Expression Program ◽  
Cardiac Stress ◽  
Cardiac Gene Expression ◽  
Left Ventricular Dilatation ◽  
Cardiac Gene ◽  
Expression Program ◽  
Deficient Mice

Myoglobin knockout mice (myo−/−) adapt to the loss of myoglobin by the activation of a variety of compensatory mechanisms acting on the structural and functional level. To analyze to what extent myo−/− mice would tolerate cardiac stress we used the model of chronic isoproterenol application to induce cardiac hypertrophy in myo−/− mice and wild-type (WT) controls. After 14 days of isoproterenol infusion cardiac hypertrophy in WT and myo−/− mice reached a similar level. WT mice developed lung edema and left ventricular dilatation suggesting the development of heart failure. In contrast, myo−/− mice displayed conserved cardiac function and no signs of left ventricular dilatation. Analysis of the cardiac gene expression profiles using 40K mouse oligonucleotide arrays showed that isoproterenol affected the expression of 180 genes in WT but only 92 genes of myo−/− hearts. Only 40 of these genes were regulated in WT as well as in myo−/− hearts. In WT hearts a pronounced induction of genes of the extracellular matrix occurred suggesting a higher level of cardiac remodeling. myo−/− hearts showed altered transcription of genes involved in carbon metabolism, inhibition of apoptosis and muscular repair. Interestingly, a subset of genes that was altered in myo−/− mice already under basal conditions was differentially expressed in WT hearts under isoproterenol treatment. In summary, our data show a high capacity of myoglobin-deficient mice to adapt to catecholamine induced cardiac stress which is associated with activation of a distinct cardiac gene expression program.

Abstract 751: Integrated Genetic Linkage Analysis and Expression Profiling in the Rat Heart to Identify Primary Drivers of Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Rizwan Sarwar ◽  
Enrico Petretto ◽  
Han Lu ◽  
Blanche Schroen ◽  
Mande K Kumaran ◽  
...  
Keyword(s):  
Gene Expression ◽  
Linkage Analysis ◽  
Cardiac Hypertrophy ◽  
Expression Profiling ◽  
Genetic Linkage ◽  
Genetic Linkage Analysis ◽  
Cardiac Gene Expression ◽  
Genome Wide ◽  
Cardiac Gene ◽  
Rat Genome

Intro: Although up to 60% of left ventricular mass (LVM) can be accounted for by extra-cardiac factors, the cause of remaining variance is uncharacterised. Hypothesis: Cardiac gene expression is under genetic control and these genetic effects account, at least in part, for the uncharacterised component of LVM. Method: We combined genetic linkage analysis with genome-wide expression profiling in a recombinant inbred (RI) rat strain panel to map the genetic determinants of cardiac gene expression, taking into account naturally occurring variation in blood pressure. Cardiac gene expression in 29 RI strains was quantified with 128 Affymetrix 230 2.0 microarrays, and linkage analysis of gene expression was performed with correction for multiple testing. Candidate genes for LVM were defined as gene colocalised with regions of the rat genome previously associated with LVM. Candidate genes identified in the rat were prioritised by assessing whether their human orthologues were dynamically regulated in heart biopsies from patients with cardiac hypertrophy undergoing surgery for aortic stenosis ( n =20) as compared to controls ( n =7), as determined with Affymetrix U133 microarrays. Results: We showed that genetic regulation of cardiac transcription is predominant when compared to extra-cardiac effects. This enabled us to determine the major control points of cardiac gene expression in the rat ( n =3,744, genome-wide P <0.05). A subset of 50 genes that mapped to themselves and colocalised with regions of the rat genome known to regulate LVM were identified. One of these 50 rat genes was mimecan or osteoglycin precursor ( Ogn ), whose orthologue showed the highest correlation with LVM out of the 22,284 probesets used in the human microarray analysis ( r =0.62, P =0.0008). We went on to refine the rat QTL associated with Ogn (peak LOD 4), and identified sequence variations that might be causative. We then showed that cardiac protein levels of OGN are increased in both rat and human hypertrophy. Conc: Combined linkage and expression studies provide a new and powerful systems approach to dissecting the pathophysiology of genetically complex traits. These data implicate Ogn as a primary genetic driver and biomarker of cardiac hypertrophy and warrant further functional testing.

Abstract 372: Master Transcriptional Regulators of Cardiac Gene Expression in Heart Failure

2018 ◽  
Vol 123 (Suppl_1) ◽  
Author(s):  
Christoph D Rau ◽  
Jessica Wang ◽  
James Ohearn ◽  
Rozeta Avetisyan ◽  
Aldons J Lusis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Transcriptional Regulators ◽  
Cardiac Gene Expression ◽  
Cardiac Gene

Epigenetic control of exercise training-induced cardiac hypertrophy by miR-208

2016 ◽  
Vol 130 (22) ◽  
pp. 2005-2015 ◽  
Author(s):  
Ursula Paula Renó Soci ◽  
Tiago Fernandes ◽  
Valerio Garrone Barauna ◽  
Nara Yumi Hashimoto ◽  
Gloria de Fátima Alves Mota ◽  
...  
Keyword(s):  
Gene Expression ◽  
Exercise Training ◽  
Cardiac Hypertrophy ◽  
Target Genes ◽  
Aerobic Training ◽  
Therapeutic Potential ◽  
Down Regulation ◽  
Epigenetic Control ◽  
Cardiac Gene Expression ◽  
Cardiac Gene

The physiological training-induced cardiac hypertrophy is epigenetically orchestrated by up-regulation of miR-208a/miR-208b and down-regulation of their target genes: Sox6, Med13, Purβ, SP3 and HP1β. These results highlight the therapeutic potential of aerobic training and miR-208 in cardiac gene expression.

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

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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