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.

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.

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.

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.

scholarly journals Impaired sarcoplasmic reticulum function leads to contractile dysfunction and cardiac hypertrophy

2001 ◽  
Vol 280 (5) ◽  
pp. H2046-H2052 ◽  
Author(s):  
Markus Meyer ◽  
Susanne U. Trost ◽  
Wolfgang F. Bluhm ◽  
Harm J. Knot ◽  
Eric Swanson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Late Phase ◽  
Cardiac Contractility ◽  
Maximum Speed ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
End Stage

Sarcoplasmic reticulum (SR)-mediated Ca2+ sequestration and release are important determinants of cardiac contractility. In end-stage heart failure SR dysfunction has been proposed to contribute to the impaired cardiac performance. In this study we tested the hypothesis that a targeted interference with SR function can be a primary cause of contractile impairment that in turn might alter cardiac gene expression and induce cardiac hypertrophy. To study this we developed a novel animal model in which ryanodine, a substance that alters SR Ca2+ release, was added to the drinking water of mice. After 1 wk of treatment, in vivo hemodynamic measurements showed a 28% reduction in the maximum speed of contraction (+dP/d t max) and a 24% reduction in the maximum speed of relaxation (−dP/d t max). The slowing of cardiac relaxation was confirmed in isolated papillary muscles. The late phase of relaxation expressed as the time from 50% to 90% relaxation was prolonged by 22%. After 4 wk of ryanodine administration the animals had developed a significant cardiac hypertrophy that was most prominent in both atria (right artrium +115%, left atrium +100%, right ventricle +23%, and left ventricle +13%). This was accompanied by molecular changes including a threefold increase in atrial natriuretic factor mRNA and a sixfold increase in β-myosin heavy chain mRNA. Sarcoplasmic endoplasmic reticulum Ca2+ mRNA was reduced by 18%. These data suggest that selective impairment of SR function in vivo can induce changes in cardiac gene expression and promote cardiac growth.

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

2006 ◽  
Vol 291 (2) ◽  
pp. H600-H611 ◽  
Author(s):  
Anthony Azakie ◽  
Jeffrey R. Fineman ◽  
Youping He
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Troponin ◽  
Troponin T ◽  
Cardiac Troponin T ◽  
Pathological Cardiac Hypertrophy ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Embryonic Cardiomyocytes

Combinatorial interactions between cis elements and trans-acting factors are required for regulation of cardiac gene expression during normal cardiac development and pathological cardiac hypertrophy. Sp factors bind GC boxes and are implicated in recruitment and assembly of the basal transcriptional complex. In this study, we show that the cardiac troponin T (cTnT) promoter contains a GC box that is necessary for basal and cAMP-mediated activity of cTnT promoter constructs transfected in embryonic cardiomyocytes. Cardiac nuclear proteins bind the cTnT GC box in a sequence-specific fashion and consist of Sp1, Sp2, and Sp3 protein factors. By chromatin immunoprecipitation, Sp1 binds the cTnT promoter “in vivo.” Cotransfected Sp1 trans-activates the cTnT promoter in cardiomyocytes in culture. Sp3 represses Sp1-mediated transcriptional activation of the cTnT gene in embryonic cardiomyocytes. Sp3 repression of Sp1-mediated cTnT promoter activation is dose dependent, inferring a mechanism of competitive binding/inhibition. To evaluate the role of Sp factors in cardiac gene expression in vivo, we have established a clinically relevant animal model of pathological cardiac hypertrophy where the fetal cardiac program is activated. In this animal model, cardiac hypertrophy results from increased left-right shunting, volume loading of the left ventricle, and pressure loading of the right ventricle. Sp1 expression is increased in all four hypertrophied cardiac chambers, whereas Sp3 expression is diminished. This observation is consistent with the in vitro activating function of Sp1 and inhibitory effects of Sp3 on activity of cTnT promoter constructs. Sp factor levels are modulated during the hypertrophic cardiac program in vivo.

scholarly journals Effect of amiodarone and dronedarone administration in rats on thyroid hormone-dependent gene expression in different cardiac components

2007 ◽  
Vol 156 (6) ◽  
pp. 695-702 ◽  
Author(s):  
I Stoykov ◽  
H C van Beeren ◽  
A F M Moorman ◽  
V M Christoffels ◽  
W M Wiersinga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Left Ventricular ◽  
Cardiac Gene Expression ◽  
Specific Effects ◽  
Cardiac Gene ◽  
The Right ◽  
Different Parts

Objective: In view of their different actions on thyroid hormone receptor (TR) isoforms we set out to investigate whether amiodarone (AM) and dronedarone (Dron) have different and/or component-specific effects on cardiac gene expression. Design: Rats were treated with AM or Dron and the expression of TRα 1, TRα 2, TRβ 1 and several tri-iodothyronine (T3)-regulated genes was studied in different parts of the heart, namely the right atrium (RA), left ventricular wall (LVW) and apex. Methods: Rats were treated for 14 days with 100 mg/kg body weight AM or Dron. The expression of TRα 1, TRα 2, TRβ 1 and T3-regulated genes was studied using real-time PCR and non-radioactive in situ hybridisation. Results: AM and Dron affected TR expression in the RA similarly by decreasing TRα 1 and β 1 expression by about 50%. In the LVW, AM and Dron decreased TRβ 1 and, interestingly, AM increased TRα 1. In the apex, AM also increased TRα 2. The changes seen in T3-dependent gene expression are reminiscent of foetal reprogramming. Conclusion: Taken together, our results indicate that AM and Dron have similar effects on the expression of TR isoforms in the RA, which could partly contribute to their ability to decrease heart rate. On the other hand, the more profound effect of AM appears on TR- and T3-dependent gene expression in the left ventricle suggests foetal reprogramming.

scholarly journals Cardiomyopathy in Irx4-Deficient Mice Is Preceded by Abnormal Ventricular Gene Expression

2001 ◽  
Vol 21 (5) ◽  
pp. 1730-1736 ◽  
Author(s):  
Benoit G. Bruneau ◽  
Zheng-Zheng Bao ◽  
Diane Fatkin ◽  
Jose Xavier-Neto ◽  
Dimitrios Georgakopoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Heart Development ◽  
Contractile Function ◽  
Specific Gene ◽  
Postnatal Life ◽  
Helix Loop Helix ◽  
And Function ◽  
Expression Program ◽  
Deficient Mice

ABSTRACT To define the role of Irx4, a member of the Iroquoisfamily of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designatedIrx4 Δex2/Δex2) was normal during embryogenesis and in early postnatal life. AdultIrx4 Δex2/Δex2 mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy,Irx4 Δex2/Δex2 hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increasedIrx2 expression, and ventricular induction of an atrial chamber-specific transgene. In neonatal hearts, ventricular expression of atrial natriuretic factor and α-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and β-myosin heavy chain accompanied adult-onset cardiac hypertrophy. Cardiac expression of Irx1, Irx2, and Irx5 may partially compensate for loss of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program. In the absence of genes under the control of Irx4, ventricular function deteriorates and cardiomyopathy ensues.

A role for T lymphocytes in mediating cardiac diastolic function

2005 ◽  
Vol 289 (2) ◽  
pp. H643-H651 ◽  
Author(s):  
Qianli Yu ◽  
Ronald R. Watson ◽  
John J. Marchalonis ◽  
Douglas F. Larson
Keyword(s):  
Gene Expression ◽  
Diastolic Function ◽  
Immune Modulation ◽  
Expression Patterns ◽  
Relative Proportion ◽  
Wall Stress ◽  
Left Ventricular ◽  
Lymphocyte Function ◽  
Cardiac Gene Expression ◽  
Cardiac Gene

The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (β) was significantly increased in the TH1 group and decreased in the TH2 group ( P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes ( P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group ( P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group ( P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.

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