Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca<sup>2+</sup>‐ATPase in mice lacking the CREM gene

Müller, Frank; Lewin, Geertje; Máťuš, Marek; Neumann, Joachim; Riemann, Burkhard; Wistuba, Joachim; Schütz, Günther; Schmitz, Wilhelm

doi:10.1096/fj.02-0486fje

Cited by 40 publications

(43 citation statements)

References 35 publications

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“…Likewise, ␣-skeletal actin was elevated. Expression of SERCA2a, a Ca 2+ -ATPase of the sarcoplasmic reticulum representing an important regulator of cardiac contraction and relaxation, is often reduced in failing hearts (Muller et al 2003). In fra-1 tg junD −/− hearts SERCA2a was slightly down-regulated (Fig.…”

Section: Subcellular and Molecular Analyses Of Heart Phenotype In Framentioning

confidence: 92%

Distinct functions of junD in cardiac hypertrophy and heart failure

Ricci¹,

Eriksson²,

Oudit³

et al. 2005

Genes Dev.

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Cardiac hypertrophic stimuli induce both adaptive and maladaptive growth response pathways in heart. Here we show that mice lacking junD develop less adaptive hypertrophy in heart after mechanical pressure overload, while cardiomyocyte-specific expression of junD in mice results in spontaneous ventricular dilation and decreased contractility. In contrast, fra-1 conditional knock-out mice have a normal hypertrophic response, whereas hearts from fra-1 transgenic mice decompensate prematurely. Moreover, fra-1 transgenic mice simultaneously lacking junD reveal a spontaneous dilated cardiomyopathy associated with increased cardiomyocyte apoptosis and a primary mitochondrial defect. These data suggest that junD promotes both adaptive-protective and maladaptive hypertrophy in heart, depending on its expression levels.Supplemental material is available at http://www.genesdev.org.

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Section: Subcellular and Molecular Analyses Of Heart Phenotype In Framentioning

confidence: 92%

Distinct functions of junD in cardiac hypertrophy and heart failure

Ricci¹,

Eriksson²,

Oudit³

et al. 2005

Genes Dev.

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“…CREM transcription factors play an important role in a variety of physiological systems including cardiac function (2,3), circadian rhythms (4) and locomotion (5). However, CREM is most notable for its role in fertility as male CREM deficient mice have a block in the maturation of sperm (6,7).…”

Section: Introductionmentioning

confidence: 99%

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Liu

Lee

Adams

et al. 2007

Bone

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CREM belongs to the ATF/CREB family of basic leucine zipper transcription factors. We previously showed that PTH induces ICER (inducible cAMP early repressor) in osteoblasts. ICER proteins, which are transcribed from the P2 promoter of the CREM gene, act as transcriptional attenuators. The objective of this study was to determine whether the Crem gene plays a role in the response of bone to intermittent PTH. Adult Crem knockout (KO) and wild type (WT) male mice were given daily subcutaneous injections of vehicle or hPTH(1-34) (160 μg/kg) for 10 days. Bone mineral content and density (BMC and BMD, respectively) were measured in femur and tibia by dual energy X-ray absorptiometry (DEXA). Bone morphometry was analyzed by X-ray computed microtomography (microCT) and histomorphometry. Serum bone turnover markers were measured. In vitro osteoclast formation assays were performed in bone marrow cultures treated with PTH or the combination of RANKL and M-CSF. KO mice had slightly higher basal bone mass than wild type mice. PTH treatment increased tibial BMC and BMD to a greater extent in WT mice compared to KO mice. PTH increased both cortical area and trabecular bone area in WT but not in KO femurs. PTH increased the bone formation rate and percent osteoblast surface to the same extent in femurs of WT and KO mice but increased osteoclast parameters and calvarial porosity to a greater extent in KO mice. PTH increased serum osteocalcin levels to the same extent in WT and KO mice. PTHinduced osteoclast formation was 2-fold greater in bone marrow cultures from KO mice. Collectively, our data suggest that the Crem deficiency in mice alters the response of bone to intermittent PTH treatment such that osteoclastogenesis is increased. Crem gene may specify the anabolic response to intermittent PTH treatment by restraining PTH-induced osteoclastogenesis.

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“…SERCA2 gene has a CRE component, and transfection of constitutively activated CRE into myocytes has been shown to stimulate SERCA2 gene transcription (24). This is supported by studies from Muller et al (28) reporting that transgenic animals lacking CRE-modulator (CREM) gene have selective downregulation of ␤-AR and SERCA2 levels, whereas transgenic mice expressing the CREM gene exhibit increased contractility and upregulation of SERCA2 levels. In rat PC13 cells, both cAMP and thyroid hormone have been reported to upregulate SERCA2 levels (40).…”

Section: Discussionmentioning

confidence: 92%

Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive G_iprotein and cAMP

Hilal-Dandan

He²,

Martin³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Hilal-Dandan R, He H, Martin JL, Brunton LL, Dillmann WH. Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive G i protein and cAMP. Am J Physiol Heart Circ Physiol 296: H728 -H734, 2009. First published January 16, 2009 doi:10.1152/ajpheart.00584.2008.-Downregulation of the sarcoplasmic reticulum calcium ATPase (SERCA2) is associated with diastolic dysfunction in the failing heart. Elevated plasma endothelin-1 (ET) levels are correlated with congestive heart failure suggesting that ET may play a pathophysiological role. We have investigated the ability of ET to regulate SERCA2 gene expression in isolated adult rat ventricular myocytes. We find that ET enhances net protein synthesis by ϳ40% but significantly downregulates SERCA2 mRNA expression, time dependently, by ϳ30 -50%, and the expression of SERCA2 protein by ϳ 50%. In myoyctes, ET binds to ET A receptor that couples to G q and Gi proteins. Inhibition of Gq-PLC-induced phosphoinositide (PI) hydrolysis with U73122 (1 M) or inhibition of G i protein with pertussis toxin (PTX) abolishes the ability of ET to downregulate SERCA2 mRNA gene expression. Further investigation suggests that ET coupling to PTX-sensitive G i with consequent lowering of cAMP is required for downregulation of SERCA2 mRNA levels. Increasing intracellular cAMP quantity using cAMP-specific PDE inhibitor Ro20-1724 or cAMP analog dibutyryl-cAMP reverses ET-induced downregulation of SERCA2 mRNA levels. The data indicate that, in adult myocytes, ET downregulates SERCA2 mRNA and protein levels, and the effect requires cross-talk between G q and PTX-sensitive G i pathways.hypertrophy; sarcoplasmic reticulum calcium ATPase; Gi; Gq THE CONTRACTION AND RELAXATION CYCLE of cardiac muscle is tightly regulated by the release and re-uptake of Ca 2ϩ . During excitation-contraction coupling, extracellular Ca 2ϩ enters the myocyte through Ca 2ϩ channels and induces Ca 2ϩ release from the sarcoplasmic reticulum (SR) to enhance contraction; subsequent Ca 2ϩ uptake via the SR Ca 2ϩ -ATPase (SERCA2) reduces intracellular Ca 2ϩ levels and facilitates muscle relaxation or diastole (4, 39). Thus cardiac muscle performance depends on the adequacy of SR and SERCA2 function.Evidence in the literature suggests that alterations in SR function and expression levels of SERCA2 mRNA correlate with prolonged and incomplete diastole in the hypertrophied and failing heart muscle (1,2,5,6,30,35,36). Decreased expression of the mRNA encoding the SERCA2 gene is associated with slower removal of cytosolic Ca 2ϩ (1,2,5,6,9,30,35,36), whereas upregulation of SERCA2 mRNA expression, induced by thyroid hormone, is associated with an increase in the rate of tension development and enhancement in the rate of relaxation (9, 34). Furthermore, increasing the expression of SERCA2 gene in transgenic animals, or in myocytes through adenovirus expressing the SERCA2 gene, results in enhanced relaxation (8,13,15).Mechanical, hormonal, and neuronal factors may c...

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Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca²⁺‐ATPase in mice lacking the CREM gene

Cited by 40 publications

References 35 publications

Distinct functions of junD in cardiac hypertrophy and heart failure

Distinct functions of junD in cardiac hypertrophy and heart failure

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive G_iprotein and cAMP

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Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+‐ATPase in mice lacking the CREM gene

Cited by 40 publications

References 35 publications

Distinct functions of junD in cardiac hypertrophy and heart failure

Distinct functions of junD in cardiac hypertrophy and heart failure

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive Giprotein and cAMP

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Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca²⁺‐ATPase in mice lacking the CREM gene

Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive G_iprotein and cAMP