Published online before print March 21, 2005, doi: 10.1161/01.CIR.0000159339.00703.22
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(Circulation. 2005;111:1510-1516.)
© 2005 American Heart Association, Inc.
Molecular Cardiology |
Adenovirus-Mediated Overexpression of Diacylglycerol Kinase-
Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy
From First Department of Internal Medicine (H.T., Y. Takeishi, T.A., H.A., Y.K., T. Shishido, Y. Tsunoda, T.N., N.N., I.K.) and Department of Anatomy and Cell Biology (H.A., Y.H., K.G.), Yamagata University School of Medicine, Yamagata, Japan; Department of Cardiology and Pneumology (T. Seidler, G.H.), Georg-August-University Goettingen, Goettingen, Germany; and Center for Cardiovascular Research (J.A.), University of Rochester, Rochester, NY.
Correspondence to Yasuchika Takeishi, MD, First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, Japan 990-9585. E-mail takeishi{at}med.id.yamagata-u.ac.jp
Received July 19, 2004; revision received November 15, 2004; accepted November 29, 2004.
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Abstract |
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Background— Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other G
q protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1–induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy.
Methods and Results— Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-
mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-, we overexpressed DGK- in cardiomyocytes using a recombinant adenovirus encoding rat DGK- (Ad-DGK). ET-1–induced translocation of PKC-
was blocked by Ad-DGK (P<0.01). Ad-DGK also inhibited ET-1–induced activation of extracellular signal-regulated kinase (P<0.01). Luciferase reporter assay revealed that ET-1–mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK- (P<0.01). In cardiomyocytes transfected with DGK-, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [3H]-leucine uptake, and increases in cardiomyocyte surface area.
Conclusions— We demonstrated for the first time that DGK- blocked ET-1–induced activation of the PKC-–ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK- might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.
Key Words: signal transduction • hypertrophy • enzymes • proteins • endothelin
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Introduction |
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Cardiac hypertrophy is a major risk factor for the development of heart failure and death.1 Identification of the signaling molecules involved in the progression of cardiac hypertrophy may lead to the development of therapeutic strategies to prevent heart failure. It has been widely recognized that heterotrimeric G
q protein-coupled receptor agonists such as endothelin-1 (ET-1), angiotensin II, phenylephrine, and others play an important role in the development of cardiac hypertrophy and progression of heart failure.2 In addition, there is substantial evidence to indicate a critical role of overactivity of the Gq protein-coupled receptor signaling pathway.3 Ligand binding to its cognate 7 transmembrane-spanning receptor activates phospholipase C-ß1 and causes cleavage of membrane-bound phosphatidylinositol biphosphate into diacylglycerol (DAG) and inositol 1,4,5-triphosphate.4 DAG is a lipid second messenger and functions as a strong activator of protein kinase C (PKC).5 PKC is a serine-threonine kinase and modulates a variety of cellular functions, including gene transcription, voltage-dependent Ca2+ channel, Na+/H+ exchanger, sarcoplasmic reticular proteins, and myofilament proteins.6 Previous studies in human heart failure and animal models of heart failure that included genetically engineered mice clearly demonstrated that activation of PKC plays a pivotal role in the development of cardiac hypertrophy and heart failure.7–11
DAG kinase (DGK) is an enzyme that is responsible for controlling the cellular levels of DAG by converting it to phosphatidic acid12 and thus is thought to act as an endogenous regulator of PKC activity. To date, 9 mammalian DGK isoforms, which differ in tissue expression and structural domains, have been identified.13,14 A previous study has indicated that 3 DGK isoforms (DGK-, DGK-, and DGK-) are expressed in adult rat myocardium,15 and the DGK- isoform is predominant; however, the functional role of DGK isoforms in cardiomyocytes remains unclear.
Therefore, in the present study, to clarify the potential roles of DGK- in the cardiomyocyte, DGK- was transiently overexpressed into cultured rat neonatal cardiomyocytes with a recombinant adenovirus that encodes rat DGK-. We studied the effects of DGK- on ET-1–induced activation of DAG-PKC signaling and resultant cardiomyocyte hypertrophy.
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Methods |
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Materials and Reagents
ET-1, BQ-123, and BQ-788 were purchased from Sigma-Aldrich Japan. [3H]-leucine was purchased from Amersham Biosciences Corp. Collagenase A, Fugene 6, and LightCycler DNA Master SYBR Green I were obtained from Roche Diagnostics Japan. The Dual-Luciferase Reporter Assay System and phRL-TK were purchased from Promega Corporation. pAP1-Luc plasmid was obtained from Stratagene. Antibodies for extracellular signal-regulated kinase (ERK) and PKC isoforms were obtained from Cell Signaling Technology, Inc, and BD Transduction Laboratories, respectively. All other chemicals were purchased from Invitrogen Corp.
Cardiomyocyte Isolation and Culture
The animals were handled according to the animal welfare regulations of Yamagata University, and the study protocol was approved by the Animal Subjects Committee of Yamagata University. The investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.
Cultured rat neonatal cardiomyocytes were prepared as described previously.16 Briefly, ventricles were obtained from 1- or 2-day-old Sprague-Dawley rats, and cardiomyocytes were isolated by digestion with collagenase. Cardiomyocytes were kept in serum-free medium (control medium) supplemented with transferrin (5 mg/mL) and insulin (1 mg/mL) for 24 hours before adenoviral infection. In this study, to induce cardiomyocyte hypertrophy, ET-1 (100 nmol/L) was added in the control medium, and cells were incubated for 48 hours.17 In some experiments, selective ETA receptor antagonist BQ-123 (10 µmol/L) or selective ETB receptor antagonist BQ-788 (10 µmol/L) was added to the medium 1 hour before the addition of ET-1.18
Adenoviral Overexpression of DGK- in Isolated Rat Neonatal Cardiomyocytes
The rat DGK- gene19,20 in vector pcDNA3.1 was cloned and ligated downstream from an immediate-early cytomegalovirus promoter into vector pACCMV.pLpA with primers to create KpnI and HindIII sites (Ad-DGK). Recombination with pJM17 plasmid and production of replication-deficient adenovirus were performed according to standard procedures as reported previously.21 Gene transfer with adenovirus encoding ß-galactosidase (Ad-LacZ) was used as an internal control.
Luciferase Assays
The plasmid pAP1-Luc that contained the firefly luciferase reporter gene driven by a basic promoter element (TATA box) joined to tandem repeats of activator protein-1 (AP1) binding element was obtained from Stratagene. As an internal control, phRL-TK that contained the renilla luciferase reporter gene driven by the herpes simplex virus-thymidine kinase promoter was used. At 24 hours after DGK transfection, cardiomyocytes were cotransfected with pAP1-Luc and phRL-TK using Fugene 6 as reported previously.22 After the preconditioning period of 24 hours, ET-1 or vehicle was added to the culture medium for 12 hours. Both firefly and renilla luciferase activities were determined in the same cell lysates with the Dual-Luciferase Reporter Assay System and MiniLumat LB9506 (Perkin-Elmer Japan Co, Ltd). Each firefly luciferase activity as AP1 transcriptional activity was corrected for differences in transfection efficiency by division with the renilla luciferase luminometric signal from the same well.22
Western Blotting for ERK Phosphorylation Activity
Cardiomyocytes were lysed in ice-cold lysis buffer, and the protein was extracted as reported previously.23,24 To examine phosphorylation activity of ERK, Western blotting was performed with an anti-phosphospecific ERK1/2 antibody as reported previously.23,24 To quantify the protein levels, the same membranes were reprobed with nonspecific anti-ERK1/2 antibody. The relative amount of phosphorylated proteins versus total proteins was used for phosphorylation kinase activity.
Protein Extraction and Separation of Membranous and Cytosolic Fractions for PKC Localization
Protein samples were extracted from the cardiomyocyte, and membranous and cytosolic fractions of detergent-extracted PKC were prepared as described previously.9,10,24 Equal amounts of membranous and cytosolic protein were subjected to electrophoresis, and the subcellular localization of PKC isoforms was examined by quantitative immunoblotting with isoform-specific antibodies as reported previously.9,10,24 Membrane/cytosol ratios of immunoreactivity were used as indices for the extent of translocation of PKC isoforms.9,10,24
Assessment of Cardiomyocyte Hypertrophy
After 48 hours’ incubation with ET-1, we measured cell surface areas using the Scion Image (Scion Corporation) as reported previously.25 At least 100 cardiomyocytes in 20 to 25 fields were examined in each experiment, and the data were averaged.
The rate of protein synthesis was determined by incorporation of [3H]-leucine as described previously.26 Briefly, cardiomyocytes (1.0x105 cells/cm2) were stimulated with ET-1 in medium supplemented with [3H]-leucine (1.0 µCi/mL). Thereafter, the cells were rinsed 3 times with ice-cold PBS and treated with 5% trichloroacetic acid (TCA) on ice for 20 minutes. After they were washed twice with ice-cold 5% TCA, cells were lysed in 0.5 N NaOH. The lysate was neutralized by 0.5 N HCl, and OPTI-FLOUR (Perkin-Elmer Japan Co, Ltd) was applied. The incorporation of [3H]-leucine was measured by a Tri-Carb Liquid Scintillation Analyzer (Perkin-Elmer Japan).
Extraction of Total RNA and Real-Time Reverse Transcription-Polymerase Chain Reaction
Total RNA was extracted from cardiomyocytes with TRIzol as described previously.27 First-strand cDNA was synthesized from 1 µg of RNA sample with oligo (dT) primers and superscript II reverse transcriptase. Real-time polymerase chain reaction (PCR) was performed with LightCycler DNA Master SYBR Green I in a 20-µL volume reaction with a light cycler (Roche Diagnostics Japan). Standard curves of DGK- and atrial natriuretic factor (ANF) amplification were generated by full-sequence plasmids of known concentrations, respectively. Variability in the initial quantities of cDNA was normalized to GAPDH. The primers used for amplification were 5-GAAGTTCAACAGCCGCTTTC-3 (forward) and 5-AGAGCCTCGTAGTCGTGCAT-3 (reverse) for DGK-, and 5-GATGGATTTCAAGAACCTGC-3 (forward) and 5-TTCAAGAGGGCAGATCTATC-3 (reverse) for ANF.15,25
Statistical Analysis
Data are expressed as mean±SEM. Comparisons among groups were performed by 1-way ANOVA followed by Fisher’s protected least significant difference test. Values with P<0.05 were considered statistically significant.
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Quantitative Analysis of DGK-
mRNA Expression After ET-1 StimulationWhether DGK-
mRNA expression is changed after stimulation with hypertrophic agonists in cardiomyocytes has not been examined previously. To quantitatively determine changes in mRNA levels of DGK- after ET-1 stimulation, we performed real-time reverse transcription (RT)-PCR analysis. As shown in Figure 1A, DGK- mRNA levels increased significantly at 1 hour (1.98±0.43-fold, P<0.05) and 3 hours (2.93±0.45-fold, P<0.01) after ET-1 stimulation and returned to basal levels after 6 hours. These results suggest that ET-1 upregulated DGK- mRNA expression in rat neonatal cardiomyocytes.
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To identify which ET receptor subtype was responsible for the induction of DGK- mRNA, we examined the effects of selective antagonists for ETA (BQ123) and ETB (BQ788) on ET-1–induced DGK- mRNA expression. ET-1–induced increases in DGK- mRNA expression were significantly inhibited by treatment with BQ123 but not by BQ788 (Figure 1B). These observations suggested that ET-1 increased DGK- mRNA expression via the ETA receptor in cardiomyocytes.
Adenovirus-Mediated Expression of DGK- in Rat Neonatal Cardiomyocytes
To examine the effect of DGK- on subcellular signaling and cardiomyocyte hypertrophy, rat neonatal cardiomyocytes were transfected with a recombinant adenovirus encoding for rat DGK- (Ad-DGK). After incubation of cardiomyocytes with Ad-DGK for 48 hours, RT-PCR and immunoblots were performed to confirm the adenovirus-mediated expression of DGK-. As shown in Figures 2A and 2B, mRNA and protein levels of DGK- rose in a dose-dependent manner. On the basis of these results, cardiomyocytes 48 hours after transfection with 20 multiplicity of infection (MOI) Ad-DGK were used for the following experiments.
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Inhibition of ET-1–Induced PKC- Translocation in Cardiomyocytes by DGK-
It has been reported that ET-1, a potent hypertrophic agonist, causes the translocation of PKC- to the membrane fraction in rat neonatal cardiomyocytes.28 Therefore, we examined the effects of Ad-DGK or Ad-LacZ on ET-1–induced translocation of PKC isoforms in cardiomyocytes using isoform-specific antibodies. As shown in Figure 3, the membrane-associated immunoreactivity of the PKC- isoform was significantly increased in ET-1–stimulated cardiomyocytes after Ad-LacZ transfection. However, translocation of PKC- and PKC-
by ET-1 was not observed in our cardiomyocyte preparations (Figures 3A and 3B). ET-1–induced translocation of PKC- was blocked after Ad-DGK transfection (membrane/cytosol ratio 4.93±0.35 versus 1.31±0.14, P<0.01), as shown in Figure 3C. These data suggest that DGK- had an inhibitory effect on ET-1–induced PKC- translocation in cardiomyocytes.
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Inhibition of ET-1–Induced ERK Activation by DGK-
We next investigated effects of Ad-DGK on ET-1–induced ERK activation. As shown in Figure 4, we observed significant ERK activation in ET-1–stimulated cardiomyocytes after Ad-LacZ transfection (3.39±1.05-fold over control, P<0.01); however, after Ad-DGK transfection, ET-1–induced ERK activation was completely abolished (0.78±0.20-fold, P<0.01). Equal protein levels of ERK were demonstrated among cardiomyocytes infected with Ad-DGK or Ad-LacZ, as shown in Figure 4. These results suggest the inhibitory effect of DGK- on ET-1–induced ERK activation in cardiomyocytes.
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Inhibition of ET-1–Induced AP1 DNA-Binding Activity
ET-1–induced activation of the PKC-–ERK pathway leads to activation of the AP1 transcription factor, thereby promoting the transcription of immediate-early genes such as c-fos and c-jun.24 Therefore, we investigated whether DGK- inhibited ET-1–induced activation of AP1 DNA-binding activity by luciferase assay. As shown in Figure 5, AP1 DNA-binding activity was significantly increased in ET-1–stimulated cardiomyocytes (4.14±0.22-fold, P<0.01). After transfection of DGK-, ET-1 did not increase AP1 DNA-binding activity, as shown in Figure 5 (1.36±0.72-fold, P<0.01). These results suggest the inhibitory effect of DGK- on ET-1–induced AP1 DNA-binding activity.
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Effects of DGK- on Hypertrophic Responses to ET-1
We then examined the effects of Ad-DGK or Ad-LacZ on hypertrophic responses to ET-1 determined by the induction of hypertrophic gene ANF, protein synthesis, and increases in cardiomyocyte surface area. Real-time RT-PCR revealed that ET-1 induced ANF gene expression after Ad-LacZ transfection (2.67±0.82-fold, P<0.01); however, Ad-DGK inhibited ET-1–induced increases in ANF gene expression levels, as shown in Figure 6A (1.13±0.20-fold, P<0.01).
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Figure 6B shows the protein synthesis evaluated by the incorporation of [3H]-leucine into cultured cardiomyocytes. Although ET-1 augmented [3H]-leucine uptake (1.33±0.06-fold, P<0.01) in control cardiomyocytes, ET-1 did not increase [3H]-leucine uptake (1.11±0.07-fold, P<0.01) in cardiomyocytes infected with Ad-DGKz.
Furthermore, we measured cardiomyocyte areas after Ad-DGK or Ad-LacZ transfection. As shown in Figure 7, ET-1 stimulation for 48 hours caused enlargement of cardiomyocyte surface area infected with Ad-LacZ (2486±57 versus 3113±64 µm2, P<0.01); however, after transfection of Ad-DGK, ET-1 did not cause increases in cardiomyocyte surface area (2653±59 µm2, P<0.01). These results suggest that DGK- blocked hypertrophic responses by ET-1.
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Discussion |
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We demonstrated that adenovirus-mediated overexpression of DGK-
inhibited the ability of ET-1 to induce the cardiomyocyte hypertrophic growth program. In cardiomyocytes transfected with Ad-DGK, ET-1 failed to induce translocation of PKC-, ERK activation, AP1 DNA-binding activation, ANF gene induction, and subsequent increases in [3H]-leucine uptake and cardiomyocyte surface area.
Increases of DGK- mRNA by ET-1 in Rat Neonatal Cardiomyocytes
DGK is a well-conserved lipid kinase that phosphorylates DAG to yield phosphatidic acid and is therefore thought to be an endogenous regulator of DAG-PKC signaling.13 To date, 9 mammalian DGK isoforms have been cloned and divided into 5 classes based on common structural motifs.14 DGK- has been isolated from cDNA libraries of rat retina and brain.19 In adult rat myocardium, it has been reported that DGK- mRNA level is increased in the area of experimental myocardial infarction in the acute phase15; that study concluded that this increase of DGK- mRNA in the infarct area might be ascribed to infiltrated macrophages and granulocytes. In the present study, we demonstrated that ET-1 increased mRNA levels of DGK- in isolated rat neonatal cardiomyocytes. To the best of our knowledge, this is the first report showing that DGK- mRNA expression is upregulated by a hypertrophic agonist in cardiomyocytes.
We also demonstrated that ET-1 increased mRNA levels of DGK- via the ETA receptor but not the ETB receptor in cardiomyocytes (Figure 1). It has been reported that cardiomyocytes predominantly express the ETA receptor.29 Consistent with expression levels in cardiomyocytes, the ETA receptor acts as a major pathway for several effects of ET-1, including myocardial contraction and hypertrophy.30 Similarly, ET-1–induced DGK- mRNA expression in cardiomyocytes was mediated via the ETA receptor in the present study. These data support the notion that DGK may play a role in regulating hypertrophic growth in response to Gq protein-coupled receptor agonists or other mechanical stimuli.
Critical Role of the DAG-PKC Signaling Pathway
It has been reported that ET-1 causes membrane translocation of PKC-, and to a lesser extent PKC-, in cultured rat neonatal cardiomyocytes.28 ET-1–induced PKC- translocation is accompanied by subsequent activation of ERK.4 In animal models of cardiac hypertrophy and heart failure by pressure overload, translocation and activation of PKC- and PKC- isoforms are observed.9,24 We have demonstrated that transgenic overexpression of a constitutively active mutant of the PKC- isoform in the mouse heart results in concentric cardiac hypertrophy.11 Conversely, overexpression of PKC-ß2 in transgenic mouse heart causes a dilated cardiomyopathy phenotype.7 Furthermore, activation of the Ca2+-sensitive PKC-, -ß1, and -ß2 isoforms is demonstrated in human end-stage heart failure.8 Therefore, it is important to regulate PKC activity and its downstream signaling pathway in the development of cardiac hypertrophy and heart failure.
Effects of Phosphatidic Acid on Cardiomyocyte Hypertrophy
Phosphatidic acid is yielded not only by DGK but also by the action of phospholipase D. Phospholipase D hydrolyzes phosphatidylcholine to form phosphatidic acid, and phosphatidic acid itself also has a signaling function. It has been reported that phosphatidic acid stimulates DNA synthesis and modulates the activity of several enzymes, including phosphatidylinositol-4-phosphate 5-kinases, ERK, and others.13,31 However, because the bulk of the signaling pool of phosphatidic acid is derived from the action of phospholipase D,32 overexpression of DGK- may not affect the phosphatidic acid pool and its signaling function. Activation of downstream ERK and protein synthesis by ET-1 were abolished by Ad-DGK in the present study (Figures 4 and 6
B). These results suggest the importance of inhibiting the DAG-PKC signaling pathway by DGK- to prevent cardiomyocyte hypertrophy.
DGK as a Regulator of the DAG-PKC Signaling Pathway
DAG is a potent activator of conventional and novel PKC subfamilies.4 As indicated in Figure 3, the PKC- isoform was translocated from a cytosolic to a membranous fraction by ET-1. The PKC- isoform belongs to the novel PKC subfamily, which is activated by DAG but not Ca2+.33 Previous studies have demonstrated the interconnectivity between PKC- and ERK signaling in cardiomyocytes.17 The AP1 is a sequence-specific transcriptional activator composed of the Jun and Fos families. Recent studies have demonstrated that myocardial AP1 DNA-binding activities are involved in experimental cardiac hypertrophy.34 ERK activation results in increased synthesis of c-Fos, which translocates to the nucleus and combines with preexisting c-Jun proteins to form AP1 dimers.35
Recently, it has been reported that PKC- inhibits DGK- in HEK293 cells.36 Activated PKC- phosphorylates DGK-, and this phosphorylation inhibits DGK activity to remove cellular DAG. In the present study with rat neonatal cardiomyocytes, PKC- was not activated by ET-1 (Figure 3A), and these results were concordant with previous reports.28 Adenovirus-mediated overexpression of DGK- also did not affect PKC- translocation (Figure 3A).
In Jurkat T cells, Zhong et al37 recently reported that overexpression of DGK- interferes with T-cell antigen receptor-induced ERK activation and AP1 induction. Luo et al38 have demonstrated spatial association of DGK- with PKC- in HEK293 cells. Recently, Verrier et al39 demonstrated that peroxisome proliferator-activated receptor-
agonists activate DGK- mRNA expression and ameliorate endothelial cell activation via the inhibition of a DAG-PKC signaling pathway. However, the functional role of any DGK isoforms in the regulation of DAG-PKC signaling has not been investigated in cardiomyocytes. In the present study, we demonstrated for the first time that DGK- inhibited the ET-1–induced hypertrophic growth program characterized by activation of the PKC-ERK-AP1 signaling pathway with resultant induction of ANF gene expression. Furthermore, DGK- abolished increases in protein synthesis and cardiomyocyte surface area by ET-1. Thus, DGK- may act as an inhibitor of a DAG-PKC signaling cascade in cardiomyocytes by controlling cellular DAG levels.
ET-1 is only one of the neurohumoral factors that mediate Gq stimulation with resultant increases in cellular DAG levels.3 Other Gq protein-coupled receptor agonists, such as angiotensin II, phenylephrine, and prostaglandin F2, also activate this cell signaling pathway by binding to their respective cognate 7 transmembrane spanning receptors.4 Therefore, the control of cellular DAG levels by DGK- might inhibit this signaling cascade more effectively than does the pharmacological blockade of each receptor.
Conclusions
The present data showed that DGK- might act as a negative regulator of hypertrophic response via inhibition of the PKC-–ERK-AP1 pathway. Because Gq protein-coupled receptor signaling plays an important role in the development of cardiac hypertrophy and the progression of heart failure, DGK- might represent a new target for the prevention and treatment of this pathological process. Future experiments generating genetically manipulated mice will further elucidate the present results obtained from cultured cardiomyocytes.
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Acknowledgments |
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This study was supported in part by grants-in-aid for scientific research (Nos. 14570635 and 16590657) from the Ministry of Education, Science, Sports and Culture, Japan, and grants from the Japan Foundation of Cardiovascular Research, The Japan Heart Foundation, The Mochida Memorial Foundation, and the German Genome Research Network.
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