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.

Multifactorial Regulation of Cardiac Gene Expression: an In Vivo and In Vitro Analysis

1995 ◽  
Vol 752 (1 Cardiac Growt) ◽  
pp. 370-386 ◽  
Author(s):  
J. L. SAMUEL ◽  
I. DUBUS ◽  
F. FARHADIAN ◽  
F. MAROTTE ◽  
P. OLIVIERO ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Vitro Analysis ◽  
In Vitro Analysis

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.

Adrenergic induction of bimodal myocardial protection: signal transduction and cardiac gene reprogramming

1999 ◽  
Vol 276 (5) ◽  
pp. R1525-R1533 ◽  
Author(s):  
Xianzhong Meng ◽  
Brian D. Shames ◽  
Edward J. Pulido ◽  
Daniel R. Meldrum ◽  
Lihua Ao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Adaptive Response ◽  
Ischemia Reperfusion ◽  
Functional Adaptation ◽  
Immunofluorescent Staining ◽  
Northern Analysis ◽  
Cardiac Gene Expression ◽  
Cardiac Gene

This study tested the hypothesis that in vivo norepinephrine (NE) treatment induces bimodal cardiac functional protection against ischemia and examined the roles of α1-adrenoceptors, protein kinase C (PKC), and cardiac gene expression in cardiac protection. Rats were treated with NE (25 μg/kg iv). Cardiac functional resistance to ischemia-reperfusion (25/40 min) injury was examined 30 min and 1, 4, and 24 h after NE treatment with the Langendorff technique, and effects of α1-adrenoceptor antagonism and PKC inhibition on the protection were determined. Northern analysis was performed to examine cardiac expression of mRNAs encoding α-actin and myosin heavy chain (MHC) isoforms. Immunofluorescent staining was performed to localize PKC-βI in the ventricular myocardium. NE treatment improved postischemic functional recovery at 30 min, 4 h, and 24 h but not at 1 h. Pretreatment with prazosin or chelerythrine abolished both the early adaptive response at 30 min and the delayed adaptive response at 24 h. NE treatment induced intranuclear translocation of PKC-βI in cardiac myocytes at 10 min and increased skeletal α-actin and β-MHC mRNAs in the myocardium at 4–24 h. These results demonstrate that in vivo NE treatment induces bimodal myocardial functional adaptation to ischemia in a rat model. α1-Adrenoceptors and PKC appear to be involved in signal transduction for inducing both the early and delayed adaptive responses. The delayed adaptive response is associated with the expression of cardiac genes encoding fetal contractile proteins, and PKC-βI may transduce the signal for reprogramming of cardiac gene expression.

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.

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.

Enhancement of glycolysis in cardiomyocytes elevates endothelin-1 expression through the transcriptional factor hypoxia-inducible factor-1 α

2002 ◽  
Vol 103 (s2002) ◽  
pp. 210S-214S ◽  
Author(s):  
Yoshihiko KAKINUMA ◽  
Takashi MIYAUCHI ◽  
Takahiko SUZUKI ◽  
Koichi YUKI ◽  
Nobuyuki MURAKOSHI ◽  
...  
Keyword(s):  
Gene Expression ◽  
Electrical Stimulation ◽  
Energy Metabolism ◽  
Hypoxia Inducible Factor ◽  
Endothelin 1 ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Cultured Cardiomyocytes

We investigated whether the type of energy metabolism directly affects cardiac gene expression. During development, the heart switches from glycolysis to fatty acid β-oxidation in vivo, as demonstrated by the developmental switching of the major isoform of myosin heavy chain (MHC) from β to α. However, the β-MHC isoform predominates in monocrotaline-induced pulmonary hypertension, a model of right ventricular hypertrophy in vivo. Cultured cardiomyocytes showed a predominance of β-MHC expression over that of α-MHC, the same pattern as in the hypertrophied heart, suggesting that the in vitro condition itself causes the energy metabolism of cardiomyocytes to be switched to glycolysis. Electrical stimulation of cultured cardiomyocytes decreased the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and hypoxia-inducible factor-1α (HIF-1α), but not that of peroxisome-proliferator-activated receptor-γ co-activator, suggesting that electrical stimulation suppresses the glycolytic system. Furthermore, a higher oxygen content (50%) decreased drastically the expression of GAPDH, HIF-1α and endothelin-1 (ET-1), and increased [3H]palmitate uptake. These findings indicate that the intrinsic energy metabolic system in cultured cardiomyocytes in vitro is predominantly glycolysis, and that the gene expression of cardiac ET-1 parallels the state of the glycolytic system. An antisense oligonucleotide against HIF-1α greatly decreased the gene expression of ET-1 and GAPDH, suggesting that cardiac ET-1 gene expression is regulated by cardiac energy metabolism through HIF-1α. In conclusion, it is suggested that the pattern of gene expression of ET-1 reflects the level of the glycolytic system in cardiomyocytes, and that enhanced glycolysis regulates the cardiac gene expression of ET-1 via HIF-1α.

Abstract 176: β-Adrenergic Receptor--Mediated Regulation of Cardiac Gene Expression Is Gefitinib Sensitive

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Douglas G Tilley ◽  
Jennifer A Talarico ◽  
Laurel A Grisanti ◽  
Rhonda L Carter
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Growth Factor Receptor ◽  
Sequencing Analysis ◽  
Egfr Transactivation ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Rapid Modulation ◽  
Acute Changes

BetaAR-mediated transactivation of epidermal growth factor receptor (EGFR) has been shown to promote cardioprotection in a mouse model of heart failure, however the mechanism(s) responsible for this pro-survival response are not known. We hypothesized that this transactivation event could impact a number of processes in the heart, including survival, via regulation of gene expression. To test the capacity of BetaAR-mediated EGFR transactivation to regulate this process, acute changes in cardiac gene expression were assessed via RNA sequencing in the hearts of C57BL/6 mice given i.p. injections of the BetaAR agonist isoproterenol (ISO, 1mg/kg) in the presence or absence of the EGFR antagonist gefitinib (Gef, 5mg/kg) for 1 hour. The total RNA from 4 hearts per treatment group (Control, ISO, Gef, Gef/ISO) were combined and underwent DNA library generation and SOLiD sequencing analysis, which revealed a substantial number of genes and isoforms regulated by each of the treatments. Interestingly, Gef alone significantly altered the expression of 270 genes compared to control suggesting potential Gef-dependent alterations in the heart during clinical use. ISO alone and Gef/ISO significantly altered 401 and 723 distinct genes compared to control, respectively. Further statistical analysis was performed between the ISO and Gef/ISO groups to assess true Gef sensitivity of ISO-regulated genes in the heart, confirming 173 genes significantly altered between the groups. Classification of these genes revealed 4 categories: ISO-dependent gene upregulation (1) or downregulation (2) antagonized by Gef, and ISO-dependent gene upregulation (3) or downregulation (4) promoted in presence of Gef. Identified within these categories were several genes known to be involved in the regulation of cardiac hypertrophy, apoptosis, sarcomeric structure and Ca2+-handling, which were selected for validation via qPCR. In conclusion, BetaAR-mediated EGFR transactivation induces rapid modulation of cardiac gene expression in response to catecholamine stimulation in vivo, with potential functional impacts on a number of cellular processes, while simultaneously acting to antagonize gene expression changes mediated via distinct BetaAR-mediated signaling pathways.

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