Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho

Hilal-Dandan, Randa; Means, Christopher K.; Gustafsson, Åsa B.; Morissette, Michael R.; Adams, John W.; Brunton, Laurence L.; Brown, Joan Heller

doi:10.1016/j.yjmcc.2003.12.010

Cited by 65 publications

(59 citation statements)

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“…EDG receptors 3, 4, and 7 were potent inducers of HDAC5 phosphorylation. These receptors, which bind lysophosphatidic acid and sphingosine-1 phosphate, respectively, have been implicated in cardiac hypertrophy (40,41) and vascular development (42,43), but the downstream signals from pathways that link these receptors to the genome have not been identified. Our results suggest that EDG signaling stimulates cardiomyocyte growth, at least in part, by promoting the phosphorylation of class II HDACs.…”

Section: Discussionmentioning

confidence: 99%

An expression screen reveals modulators of class II histone deacetylase phosphorylation

Chang

Bezprozvannaya

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Class II histone deacetylases (HDACs) repress transcription by associating with a variety of transcription factors and corepressors. Phosphorylation of a set of conserved serine residues in the N-terminal extensions of class II HDACs creates binding sites for 14-3-3 chaperone proteins, which trigger nuclear export of these HDACs, thereby derepressing specific target genes in a signaldependent manner. To identify intracellular signaling pathways that control phosphorylation of HDAC5, a class II HDAC, we designed a eukaryotic cDNA expression screen in which a GAL4-dependent luciferase reporter was expressed with the DNAbinding domain of GAL4 fused to the N-terminal extension of HDAC5 and the VP16 transcription activation domain fused to 14-3-3. The transfection of COS cells with cDNA expression libraries results in activation of luciferase expression by cDNAs encoding HDAC5 kinases or modulators of such kinases that enable phosphorylated GAL4 -HDAC5 to recruit 14-3-3-VP16 with consequent reconstitution of a functional transcriptional complex. Our results reveal a remarkable variety of signaling pathways that converge on the signal-responsive phosphorylation sites in HDAC5, thereby enabling HDAC5 to connect extracellular signals to the genome.endothelial differentiation genes ͉ lysophosphatidic acid receptors ͉ Rho signaling ͉ sphingosine-1 phosphate C hanges in histone acetylation represent a key mechanism for the modulation of gene transcription (1). Acetylation of nucleosomal histones by histone acetyltransferases enhances transcription by relaxing the condensed structure of the nucleosome, whereas deacetylation of histones by histone deacetylase (HDAC) activity reverses this process and promotes chromatin condensation and transcriptional repression. The recruitment of histone acetyltransferases and HDACs by specific transcription factors enables these chromatin-modifying enzymes to regulate specific sets of target genes.

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Section: Discussionmentioning

confidence: 99%

An expression screen reveals modulators of class II histone deacetylase phosphorylation

Chang

Bezprozvannaya

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…We have previously reported that expression of constitutively active form of G ␣i2 (mG i ), packaged into adenoviral vectors, in myocytes can induce hypertrophy (16). When mGi was expressed in cultured adult myocytes, the levels of both SERCA2 mRNA (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported that, in adult myocytes, ET activates G q -phospholipase C pathways to induce PI hydrolysis and activation of PKC ␦ and ⑀ and the MAPK cascade (19,33). Several studies indicate that G q -coupled signaling, phorbol ester stimulation, specific activation of PKC ␦ and ⑀ isoforms, and activation of Raf/MEK/MAPK pathways (14,16,20,31,44) can downregulate SERCA2 mRNA gene expression. Thus our data support a role for ET-coupled G q -PLC pathway in mediating downregulation of SERCA2 mRNA gene expression levels in myocytes.…”

Section: Discussionmentioning

confidence: 99%

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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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“…In 1993, Banach et al (2) first reported that serum contains a PTX-sensitive lipid factor that could antagonize ␤-AR-stimulated AC activity on L-type Ca 2ϩ channels. Later studies by this group (and others) demonstrated that S1P and other related molecules (e.g., sphingosylphosphorylcholine and lysophosphatidic acid) could depress contractility by inhibiting I CaL and/or by activating an I K ACh -like K ϩ current in myocytes (1,11,16,19,33,43). These important findings on S1P-induced negative inotropic effects and/or bradycardia have been replicated in a number of animal species, including rabbit (16), cats (44), rats (39), mice (14), and guinea pigs (43).…”

Section: Discussionmentioning

confidence: 97%

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

Landeen

Dederko²,

Kondo³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Landeen LK, Dederko DA, Kondo CS, Hu BS, Aroonsakool N, Haga JH, Giles WR. Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 294: H736-H749, 2008. First published November 16, 2007 doi:10.1152/ajpheart.00316.2007.-Sphingosine-1-phosphate (S1P) induces a transient bradycardia in mammalian hearts through activation of an inwardly rectifying K ϩ current (IK ACh ) in the atrium that shortens action potential duration (APD) in the atrium. We have investigated probable mechanisms and receptor-subtype specificity for S1P-induced negative inotropy in isolated adult mouse ventricular myocytes. Activation of S1P receptors by S1P (100 nM) reduced cell shortening by ϳ25% (vs. untreated controls) in fieldstimulated myocytes. S1P 1 was shown to be involved by using the S1P 1-selective agonist SEW2871 on myocytes isolated from S1P3-null mice. However, in these myocytes, S1P 3 can modulate a somewhat similar negative inotropy, as judged by the effects of the S1P 1 antagonist VPC23019. Since S1P1 activates Gi exclusively, whereas S1P 3 activates both Gi and Gq, these results strongly implicate the involvement of mainly G i. Additional experiments using the IK ACh blocker tertiapin demonstrated that IK ACh can contribute to the negative inotropy following S1P activation of S1P 1 (perhaps through Gi␤␥ subunits). Mathematical modeling of the effects of S1P on APD in the mouse ventricle suggests that shortening of APD (e.g., as induced by I K ACh ) can reduce L-type calcium current and thus can decrease the intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) transient. Both effects can contribute to the observed negative inotropic effects of S1P. In summary, these findings suggest that the negative inotropy observed in S1P-treated adult mouse ventricular myocytes may consist of two distinctive components: 1) one pathway that acts via G i to reduce L-type calcium channel current, blunt calcium-induced calcium release, and decrease [Ca 2ϩ ]i; and 2) a second pathway that acts via Gi to activate IK ACh and reduce APD. This decrease in APD is expected to decrease Ca 2ϩ influx and reduce [Ca 2ϩ ]i and myocyte contractility.calcium; contraction; cell shortening; inhibitory G protein; acetylcholine-sensitive potassium; myocyte SPHINGOSINE-1-PHOSPHATE (S1P) is a biologically active, cell membrane-associated sphingolipid that binds with high affinity to five distinct G-coupled protein receptor isoforms (S1P 1-5 ). S1P 1 has been detected in abundance in neonatal rat cardiomyocytes (39). In these cells, exposure to S1P (500 nM) results in an initial negative inotropic effect (reduction of systolic calcium). However, this may be followed by calcium overload (increased diastolic calcium) and then a cessation of contractility. In isolated atrial myocytes, S1P has been shown to activate a weakly inwardly rectifying potassium (K ϩ ) current. This K ϩ conductance is very similar to the K ϩ current activated by ACh (I K ACh ). Activation of this current can shorte...

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Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho

Cited by 65 publications

References 50 publications

An expression screen reveals modulators of class II histone deacetylase phosphorylation

An expression screen reveals modulators of class II histone deacetylase phosphorylation

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

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

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Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho

Cited by 65 publications

References 50 publications

An expression screen reveals modulators of class II histone deacetylase phosphorylation

An expression screen reveals modulators of class II histone deacetylase phosphorylation

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

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

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