© 1997 American Heart Association, Inc.
Articles |
Angiotensin II Stimulates c-Jun NH2-Terminal Kinase in Cultured Cardiac Myocytes of Neonatal Rats
the Department of Medicine III (S.K., I.K., T.M., T.Y., Y.Z., I.S., Y.Y.), University of Tokyo (Japan) School of Medicine; the Health Service Center (T.Y.), University of Tokyo; and the Department of Cardiology (N.T.), Kanazawa (Japan) Medical University.
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Abstract |
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Many lines of evidence have suggested that angiotensin II (Ang II) plays an important role in cardiac hypertrophy. Ang II not only increases protein synthesis but also induces the reprogramming of gene expression in cultured cardiac myocytes. In the present study, to elucidate the mechanism by which Ang II regulates gene expression in cardiac myocytes, we examined whether Ang II activates c-Jun NH2-terminal kinase (JNK), which is a member of the mitogen-activated protein kinase family and activates the transcription factor, activator protein-1 (AP-1). The activity of JNK increased 5 minutes after the addition of Ang II, peaked at 20 minutes, and gradually decreased thereafter. Examination of the Ang II dose-response relation revealed detectable JNK activation at 10-9 mol/L and maximal activation at 10-6 mol/L. Ang II activated JNK through the AT1 receptor, and the activation was attenuated by the downregulation of protein kinase C or the chelation of intracellular Ca2+. Although the addition of either Ca2+ ionophore or phorbol ester resulted in little or no activation of JNK, simultaneous addition of both Ca2+ ionophore and phorbol ester markedly activated JNK. Slight expressions of the c-jun gene were observed in unstimulated cardiac myocytes, and Ang II increased expressions of the c-jun gene as well as the c-fos gene. Ang II increased transcription of the endothelin-1 gene through the AP-1 binding site. In conclusion, Ang II may activate JNK in cultured cardiac myocytes through an increase in intracellular Ca2+ and activation of protein kinase C, and the activated JNK may regulate gene expression by activating AP-1 during Ang II–induced cardiac hypertrophy.
Key Words: angiotensin II • c-Jun NH2-terminal kinase • cardiac myocyte • protein kinase C • Ca2+
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Introduction |
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Cardiac myocytes, which lose their proliferative ability after birth, respond to a variety of stimuli by hypertrophy. During cardiac hypertrophy, cardiac myocytes dramatically change the pattern of gene expressions and enhance protein synthesis, resulting in increased efficiency of contraction and decreased wall stress.1 Recently, the concept of cardiac hypertrophy has been challenged. Clinical studies have suggested that cardiac hypertrophy is not only an adaptational state prior to cardiac failure but also an independent risk factor of cardiac morbidity and mortality.2 Thus, it has become even more important to understand the underlying mechanisms of cardiac hypertrophy.
Cardiac hypertrophy is induced by hemodynamic overload1 and a variety of neurohumoral factors, such as catecholamines,3 Ang II,4 and ET-1.5 A growing body of data suggests that the local renin-angiotensin system plays an important role in the development of cardiac hypertrophy.6 All components of the renin-angiotensin system have been identified in the heart at both mRNA and protein levels.7 Ang II increases hydrolysis of phosphoinositides, resulting in the activation of PKC, and enhances protein synthesis in cultured cardiac myocytes.8 9 Many recent reports have also demonstrated that the cardiac renin-angiotensin system is activated in experimental left ventricular hypertrophy induced by hemodynamic overload. Increases in angiotensinogen and ACE mRNAs have been reported in the hypertrophied left ventricle of rats.10 Subpressor doses of ACE inhibitors can cause regression of cardiac hypertrophy with no change in systemic systolic blood pressure.11 Moreover, our and other laboratories have demonstrated that stretching cultured cardiac myocytes induces secretion of Ang II and that the Ang II evokes a variety of intracellular signals, followed by the expression of specific genes and an increase in protein synthesis.12 13 14 The early genetic response to Ang II in cardiac myocytes includes transcription of a number of IEGs, such as c-fos, c-myc, c-jun, and Egr-1.1 9 Ang II later induces the reprogramming of gene expression and stimulates expressions of "fetal" genes, which are usually expressed during the fetal stage.
JNK, also called SAPK, is a subfamily of the MAPK family of serine/threonine kinases.15 16 17 Unlike the related 42- and 44-kD ERKs (ERK-1 and ERK-2), JNK is weakly activated by growth factors and phorbol esters, such as TPA, but markedly activated in response to the inflammatory cytokine, tumor necrosis factor-
, ultraviolet irradiation, and a variety of cellular stresses, such as heat shock, osmotic shock, and ischemia/reperfusion.16 17 18 19 20 JNK phosphorylates c-Jun and ATF-2 at putative regulatory amino-terminal serine residues and increases their transcriptional activities.16 17 21 c-Jun is one of the major components of the transcription factor, AP-1, which regulates expression of many genes having a TRE in their promoter regions.22 ATF-2 dimerizes not only with c-Jun but also with members of the ATF family (including ATF-2 and ATF-3), the cAMP response element binding protein, and nuclear factor-
B,21 and these dimers may regulate a number of genes. Recent evidence suggests that JNK enhances DNA binding and transcriptional activity of the ternary complex factor, Elk-1.23 Elk-1, together with serum response factor, controls transcription of many IEGs, including c-fos and Egr-1. In the present study, to elucidate the mechanism of Ang II–induced gene expression in cardiac myocytes, we have tested whether Ang II increases the activity of JNK.
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Materials and Methods |
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-32P]ATP was purchased from Du Pont-New England Nuclear Co; DMEM and FCS, from GIBCO BRL Co; and polyclonal antibody against JNK, from Santa Cruz Biotechnology, Inc. Other reagents were purchased from Sigma Chemical Co. CV-11974 and PD123319 were kind gifts from Takeda Chemical Industries, Ltd (Osaka, Japan) and Parke-Davis (Ann Arbor, MI), respectively.
Cell Culture of Cardiac Myocytes
Primary cultures of cardiac myocytes were prepared from ventricles of 1-day-old Wistar rats, as described previously,24 basically according to the method of Simpson.3 Cardiac myocytes were plated at a field density of 1x105 cells/cm2 on 3.5-cm dishes. The culture medium was changed 24 hours after seeding from DMEM containing 10% FCS to DMEM containing 0.1% FCS (low-serum condition). Immunocytochemical analysis using anti–myosin heavy chain antibody revealed that >90% of the cells were cardiac myocytes.
JNK Assay
Forty-eight hours after cells were cultured under the low-serum condition, cardiac myocytes were stimulated by the indicated experimental drugs at 37°C. After being washed with ice-cold PBS, cells were lysed with 100 µL of ice-cold lysis buffer A containing 250 mmol/L NaCl, 3 mmol/L EDTA, 3 mmol/L EGTA, 0.5% NP-40, 20 mmol/L Tris-HCl (pH 7.6), 100 mmol/L sodium orthovanadate, 3 mmol/L ß-glycerophosphate, 10 µg/mL leupeptin, and 1 mmol/L phenylmethylsulfonyl fluoride. The lysates were obtained by centrifugation at 12 000 rpm for 20 minutes at 4 °C. Kinase activity of JNK was determined by the immune complex kinase assay using an anti-JNK polyclonal antibody (purchased from Santa Cruz Biotechnology, Inc), raised against full-length human JNK1 produced in Escherichia coli. Cell lysates were incubated with 2 µg of the anti-JNK antibody at 4°C for 12 hours and then incubated with 50 µL of protein A–Sepharose at 4°C for 40 minutes. The mixtures were centrifuged briefly and washed twice with ice-cold lysis buffer. Each sample was mixed with 1 µg of the GST–c-Jun (1-79) protein in 8 µL of kinase reaction buffer containing 25 mmol/L Tris-HCl (pH 7.4), 10 mmol/L MgCl2, 1 mmol/L dithiothreitol, 0.5 mmol/L EGTA, 40 µmol/L ATP, and 1 µCi [-32P]ATP and incubated at 30°C for 30 minutes. The GST–c-Jun (1-79) fusion construct was made by inserting the human c-Jun NH2-terminal portion (amino acid number 1-79) into the pGEX-2T vector (Pharmacia) in frame.16 The fusion protein was made as previously reported.25 The reaction mixtures were centrifuged briefly, and the pellet was washed with ice-cold lysis buffer. The samples were electrophoresed on 12% polyacrylamide gels. The gels were dried and subjected to autoradiography. The intensity of phosphorylated bands was analyzed by densitometric scanning. The activity of JNK was also measured by using GST–c-Jun (1-79) protein–containing gel.20 The cell lysates were electrophoresed on the GST–c-Jun (1-79) protein–containing SDS-polyacrylamide gel. JNK was denatured by treating the gel with 6 mol/L guanidine-HCl and renatured in 50 mmol/L Tris-HCl (pH 8.0) containing 0.04% Tween 40 and 5 mmol/L 2-mercaptoethanol. Phosphorylation of GST–c-Jun (1-79) protein was assayed by incubating the gel with [-32P]ATP. After incubation, the gel was washed, dried, and then subjected to autoradiography.
ERK Assays in MBP-Containing Gels After SDS-PAGE
ERK assays in MBP-containing gels were performed as described previously.14 In brief, cardiac myocytes were lysed with buffer B containing 25 mmol/L Tris-HCl, 25 mmol/L NaCl, 1 mmol/L sodium orthovanadate, 10 mmol/L NaF, 10 mmol/L sodium pyrophosphate, 10 nmol/L okadaic acid, 0.5 mmol/L EGTA, and 1 mmol/L phenylmethylsulfonyl fluoride. Aliquots of the extracts were electrophoresed on an SDS-polyacrylamide gel containing 0.5 mg/mL MBP. After SDS was removed, the enzyme was denatured by treating the gel with 6 mol/L guanidine-HCl and renatured with 50 mmol/L Tris-HCl (pH 8.0) containing 0.04% Tween 40 and 5 mmol/L 2-mercaptoethanol. Phosphorylation of MBP was carried out by incubating the gel with 25 µCi [-32P]ATP. The washed gel was dried and then subjected to autoradiography.
RNA Preparation and Northern Blot Analysis
After stimulation, cultured cardiac myocytes were washed twice with ice-cold PBS, and RNAs were prepared using zolB (Cinna Biotecx Laboratories, Inc) according to the manufacturer's instructions. Total RNA (20 µg) was fractionated in 1% formaldehyde agarose gels and transferred to nylon membranes. The blots were hybridized with the full-length cDNA fragment of human c-fos and c-jun cDNA26 as described previously.24
Reporter Gene Assays
Three TRE sequences are linked tandemly and inserted into the thymidine kinase minimal promoter–containing luciferase vector.27 ET-1 reporter fusion plasmids contained the luciferase gene in conjunction with the ET-1 5' promoter sequence. The reporter plasmid (-204 ET-LUC) contained 204 bp of the wild-type ET-1 promoter. A reporter plasmid with mutations in the TRE site (mut TRE) was derived from -204 ET-LUC by polymerase chain reaction–based site-directed mutagenesis.28 In the mut TRE reporter, the wild-type sequence GTGACTAA was altered to GGTACTCAA. The sequence of each of the mutated polymerase chain reaction fragments was confirmed by sequencing. Three micrograms of (TREx3)-luciferase reporter plasmid, ET-LUC, or mut TRE ET-LUC was transfected into cardiac myocytes using lipofectin (Tfx-50, Promega), according to the manufacturer's instructions. Two hours later, the cells were washed twice with PBS and cultured in the serum-free media for 48 hours. Cells were incubated with Ang II (10-6 mol/L) for 4 hours and lysed in situ. The luciferase activities were determined using a luminometer (Luminoscan, Labsystems).29 An expression plasmid containing ß-galactosidase was cotransfected as an internal control of the transfection efficiency, and data were normalized to the ß-galactosidase activity. All transfection experiments were performed four times.
Statistics
Differences within groups were compared by one-way ANOVA and Dunnett's t test. The accepted level of significance was P<.05.
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Ang II Increases Activity of JNK
After cardiac myocytes were stimulated with Ang II (10-6 mol/L) for 30 minutes, cell lysates were extracted, and activity of JNK was measured by the immune complex kinase assay using the GST–c-Jun (1-79) fusion protein. Ang II markedly increased the activity of JNK (Fig 1
, left). JNK exists in two forms, 46 kD (JNK1) and 55 kD (JNK2) in size, both of which have been reported to be activated by external stimuli.20 To elucidate which type of JNK is activated by Ang II, we performed "in-gel" analysis. The lysates were electrophoresed on the SDS-polyacrylamide gel containing GST–c-Jun (1-79) fusion proteins, and phosphorylation of c-Jun protein was assayed by incubating the gel with [-32P]ATP. Some basal activities of both JNKs were observed in unstimulated cardiac cells, and Ang II strikingly increased the activities of both 46- and 55-kD JNKs (Fig 1, right). Densitometric scanning of each band revealed that the activity of 46- and 55-kD JNK increased 1.9- and 4.1-fold, respectively, compared with unstimulated control.
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Time Course of Activation of JNK by Ang II
We examined the time course of activation of JNK by Ang II. The increase in JNK activity was first detected at 5 minutes after the addition of Ang II, peaked at 20 to 30 minutes, and gradually decreased thereafter (Fig 2). One hour after the addition of Ang II, the activity of JNK returned to basal levels. This time course of JNK activation by Ang II is quite different from that of ERKs. Activation of ERK-1 by Ang II was more rapid and transient (Fig 2, bottom)14 . The increase in activity of ERK-1 was detected from as early as 2 minutes, peaked at 8 minutes, and returned to basal levels within 30 minutes.
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) and ERK-1 (
) are shown as percent increase in the average from four independent experiments compared with unstimulated controls (100%).
Ang II Dose-Dependently Activates JNK
Cardiac myocytes were incubated with various concentrations (10-10 to 10-6 mol/L) of Ang II. No significant increase in JNK activity was observed at 10-10 mol/L Ang II compared with the vehicle (control). Although JNK activation by Ang II was variable, a dose-dependent increase in activity of JNK by Ang II stimulation was observed between 10-9 and 10-6 mol/L (Fig 3). Maximum activation of JNK was obtained by the addition of 10-6 mol/L Ang II. The activity of JNK stimulated by 10-5 mol/L Ang II was almost the same as that stimulated by 10-6 mol/L Ang II (data not shown).
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Ang II Activates JNK Through AT1 Receptors
Two main subtypes of Ang II receptors, AT1 and AT2 receptors, have been identified pharmacologically, and the cDNA corresponding to each receptor has been recently isolated.30 31 32 33 We have previously demonstrated that activation of ERK-1 and ERK-2 by Ang II is mediated through the AT1 receptor in cardiac myocytes.14 To identify which subtype of the Ang II receptor is involved in JNK activation, we preincubated cells with CV-11974 (10-6 mol/L, AT1 receptor–specific antagonist), PD 123319 (10-7 mol/L, AT2 receptor–specific antagonist), and saralasin (10-6 mol/L, antagonist of both AT1 and AT2 receptors) for 30 minutes and then added Ang II to cardiac myocytes. Both CV-11974 and saralasin completely abolished JNK activation induced by Ang II; however, PD 123319 had no significant effects on JNK activation (Fig 4). These results suggest that Ang II activates JNK through AT1 receptor–like ERKs in cardiac myocytes.
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PKC and Ca2+ Are Involved in Activation of JNK by Ang II
PKC and intracellular Ca2+ have been reported to be major signals through the AT1 receptor.6 7 14 To obtain insights into the mechanism by which Ang II activates JNK, we examined the role of PKC and Ca2+ in Ang II–induced activation of JNK. Cultured cardiac myocytes were treated for 24 hours with 100 nmol/L TPA, which depletes TPA-sensitive PKC activity and abolishes the PKC-dependent activation of ERKs in these cells.14 In TPA-treated cells, activation of JNK by Ang II was strikingly attenuated (Fig 5). Although chelation of extracellular Ca2+ by 1 mmol/L EGTA had no effects on the activation of JNK by Ang II, BAPTA-AM (10 µmol/L), which chelates intracellular Ca2+, suppressed activation of JNK (Fig 5). When 1 µmol/L TPA was added to cultured cardiac myocytes, activity of JNK was slightly (
2.0-fold) increased (Fig 6). The addition of a Ca2+ ionophore, A23187, did not produce a significant increase in the activity of JNK. When both TPA and A23187 were added to the cultured cardiac myocytes at the same time, however, the activity of JNK was markedly (3.5-fold) increased (Fig 6).
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Ang II Induces Expression of c-fos and c-jun Genes and Activates TRE-Containing Promoter
JNK has been reported to phosphorylate two serine residues in the presumptive activation domain of c-Jun and to increase its transcriptional activity.15 16 17 34 35 c-Jun forms a homodimer or a heterodimer with the Fos family, thus forming the transcription factor, AP-1, and transactivates many genes that have a TRE in their promoter regions.35 The transcription of the c-jun gene itself is also controlled by AP-1.35 As reported previously,9 36 Ang II rapidly and transiently activates c-fos gene expression (Fig 7, top left). Slight expression of the c-jun gene was observed in unstimulated cultured cardiac myocytes, and expression levels of the c-jun gene were markedly elevated by Ang II (Fig 7, bottom left). The peak of c-jun expression was observed at 60 minutes, which is later than that of c-fos expression (Fig 7, left panels), suggesting that the mechanism of gene induction may be different between c-fos and c-jun. Since activated c-Jun has been reported to transactivate the genes that contain a TRE in their promoter region,22 we examined whether Ang II activates the transcription of a TRE-containing gene. We first transfected a luciferase reporter gene containing thymidine kinase minimum promoter and three TRE sequences into cardiac myocytes and stimulated cardiac myocytes by Ang II. Ang II increased the luciferase activity of the TRE-containing reporter gene by 2.4-fold (Fig 7, top right). We next asked whether Ang II actually activates expressions of cardiac genes through TRE sequences by using the ET-1 promoter, whose activity is known to depend on TRE.28 The luciferase activity of -204 ET-LUC was increased by the addition of Ang II (wild in Fig 7, bottom right), whereas the luciferase activity of the gene containing the mutation in the TRE site (mut TRE ET-LUC) was not enhanced by Ang II (mutant in Fig 7, bottom right). These results suggest that Ang II activates transcription of the ET-1 gene through TRE.
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Discussion |
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Although cardiac myocytes lose their proliferative ability after birth, they respond to a variety of external stimuli by changing the pattern of gene expression during cardiac hypertrophy.1 Many laboratories have reported that Ang II plays an important role in cardiac hypertrophy.4 5 6 7 8 9 10 11 12 13 14 Ang II induces expression of IEGs and the fetal type of genes and increases protein synthesis in cultured cardiac myocytes.1 4 6 7 8 9 36 External stimuli are generally transduced into the nucleus through the protein kinase cascade of phosphorylation. We9 14 and others6 8 have reported that Ang II activates PKC, Raf-1, MAPK kinase, ERKs, and p90rsk. In the present study, we have demonstrated that Ang II activates JNK, which is a subfamily of the MAPK group and is weakly activated by growth factors but markedly activated by TNF-
and a variety of cellular stresses.15 16 17 18 19 20 Unlike many ligands that stimulate primarily either JNK or ERKs, Ang II effectively stimulated both JNK and ERKs in cardiac myocytes (Fig 2
). Recently, it has been reported that JNK is activated by G protein–coupled receptors, such as the m1 class of muscarinic acetylcholine receptors in NIH 3T3 cells,37 Ang II receptors in GN4 rat liver epithelial cells,38 and ET-1 receptors in cultured ventricular myocytes.39 Since stimulation of these G protein–coupled receptors also activates ERKs, it is possible that, unlike growth factor receptors, G protein–coupled receptors may generally activate both JNKs and ERKs. We have recently reported that mechanical stress activates JNKs as well as ERKs in cultured cardiac myocytes,40 although it has not been known whether mechanical stress evokes signals through G proteins.
Quite recently, it has been reported that Ang II activates JNK in GN4 rat liver epithelial cells in a Ca2+-dependent PKC-independent manner.38 In GN4 cells, Ca2+ ionophores stimulated a dramatic increase in JNK activity, and PKC depletion had no effect on Ang II–induced JNK activation. A tyrosine kinase inhibitor, genistein, prevented Ang II–induced JNK activation as well as Ca2+-dependent tyrosine phosphorylation in the liver cells.38 In cardiac myocytes, activation of JNK by Ang II was strongly suppressed by downregulation of PKC or chelation of intracellular Ca2+ (Fig 5). Either the activation of PKC or an increase in Ca2+ was insufficient to efficiently activate JNK, but the simultaneous addition of both TPA and A23187 markedly increased the activity of JNK in cardiac myocytes (Fig 6). In T lymphocytes, JNK is activated by the stimulation from two major signaling pathways, one of which can be triggered by phorbol esters (such as TPA) and the other by Ca2+ ionophores (such as A23187).20 Thus, the second messengers that are involved in the JNK activation may be different among cell types, and two signaling pathways, such as PKC and Ca2+, may be important for the activation of JNK in cardiac myocytes as well as in T lymphocytes. It is interesting to examine whether activation of Ca2+-dependent tyrosine kinase also plays an important role in Ang II–induced JNK activation in cardiac myocytes.
We have observed that mechanical stress and Ang II activate phosphorylation cascades of protein kinases, including MEKK in cardiac myocytes.41 Recently, it has been reported that MEKK activates JNK through SAPK/ERK kinase-1.42 Many lines of evidence have suggested that a small GTP binding protein, Ras, plays critical roles in proliferation and differentiation by activating the Raf-1/ ERK cascade in a variety of cell types, including cardiac myocytes.43 44 Quite recently, it has been reported that the small GTP binding proteins of the Rho family, Rac1 and Cdc42, regulate the activity of JNK.45 46 Although the Rho-like proteins were hitherto thought to function in the regulation of cell morphology,47 Rac1 and Cdc42 have been demonstrated to bind to the p21-activated serine/threonine kinase PAK65 and stimulate its autophosphorylation activity.48 49 Taken together, Ang II may activate both cascades of Raf-1/ERKs and MEKK/JNKs through different small GTP binding proteins. The investigation using inhibitory molecules for Rho-related GTPases is now in progress to prove this hypothesis.
ERKs have been reported to phosphorylate the ternary complex factor, Elk-1, which controls the expression of the c-fos gene.50 51 It has been demonstrated that JNK phosphorylates c-Jun and ATF-2 at the putative regulatory amino-terminal serine residues and increases their transcriptional activities.16 17 21 Moreover, JNK has been reported to activate Elk-1,23 resulting in the increase in c-fos gene expression. c-Fos and c-Jun make the heterodimer complex called AP-1, which transactivates many genes that have a TRE in their promoter.22 It has been reported that many genes, including genes of c-jun,52 atrial natriuretic peptide,53 and ET-1,28 54 contain a TRE in their promoter regions and that AP-1 regulates the transcription of these genes. These genes increase their transcription levels during cardiac hypertrophy.1 53 54 In the present study, we observed slight expressions of the c-jun gene in unstimulated cultured cardiac myocytes (Fig 7, bottom left). Collectively, JNK may be involved in the Ang II–induced increase in c-jun mRNA levels by activating the preexisting Jun protein. We showed that transcription of the ET-1 gene was actually activated by Ang II through TRE. In addition, since ATF-2 can dimerize with many proteins, such as the ATF family and nuclear factor-B, the activation of JNK may influence the transcription of numerous genes. Further investigations are necessary to elucidate which genes enhance their transcriptions via activating JNK during cardiac hypertrophy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant-in-aid for scientific research and developmental scientific research from the Ministry of Education, Science, and Culture; a grant from the Japan Cardiovascular Foundation; the Sankyo Life Science, Yamanouchi, Tanabe Medical Frontier Conference; and the Study Group of Molecular Cardiology (to Dr Komuro). We acknowledge Takeda Chemical Industries, Ltd (Osaka, Japan) and Parke-Davis (Ann Arbor, Mich) for providing CV-11974 and PD123319, respectively. We thank Drs Masahiko Hibi and Masatoshi Kawana for plasmids and Fumiko Harima and Makiko Iwata for their excellent technical assistance.
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Footnotes |
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Reprint requests to Issei Komuro, MD, PhD, Molecular Cardiology Division, Department of Medicine III, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky@umin.u-tokyo.ac.jp
Received September 23, 1996; accepted November 1, 1996.
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