Abstract
Although MAP (mitogen-activated protein) kinases are implicated in cell proliferation and differentiation in many cell types, the role of MAP kinases in cardiac hypertrophy remains unclear. We examined the role of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAP kinase in angiotensin II (Ang II)-induced hypertrophy compared with phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. Both Ang II and phenylephrine activated ERKs to a similar extent, whereas phenylephrine caused stronger and more sustained activation of JNK and p38 than Ang II. PD98059, a specific inhibitor of MAPK/ERK kinase (MEK),inhibited Ang II-induced, but not phenylephrine-induced, expression of atrial natriuretic factor (ANF) at both the mRNA and polypeptide levels. SB203580, a specific inhibitor of p38 and some JNK isoforms, did not show significant effects on ANF expression induced by Ang II or phenylephrine. Although PD98059 and dominant-negative MEK1 blocked Ang II-induced activation of the ANF promoter, SB203580 or dominant-negative MEK kinase 1 (MEKK1) showed no effect. Phenylephrine-induced ANF promoter activation was significantly inhibited by SB203580 and dominant-negative MEKK1, but not by PD98059 or dominant-negative MEK1. Dominant-negative Ras inhibited both ERK activation and ANF up-regulation by Ang II, whereas constitutively active forms of Ras and MEK were sufficient to activate the ANF promoter. Dominant-negative Ras also partly inhibited the phenylephrine-induced activation of ANF promoter. PD98059 did not affect other markers of Ang II-induced hypertrophy, such as skeletal alpha-actin and c-fos expression, increases in the rate of protein synthesis or rapid sarcomeric actin organization. These results suggest that Ang II uses ERK for ANF expression, whereas phenylephrine uses other pathways. The Ras/ERK pathway selectively mediates ANF expression in various phenotypes observed in Ang II-induced hypertrophy. The ERK pathway mediates an agonist-specific and phenotype-specific response in cardiac hypertrophy.
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- Adams J. W., Sah V. P., Henderson S. A., Brown J. H. Tyrosine kinase and c-Jun NH2-terminal kinase mediate hypertrophic responses to prostaglandin F2alpha in cultured neonatal rat ventricular myocytes. Circ Res. 1998 Jul 27;83(2):167–178. doi: 10.1161/01.res.83.2.167. [DOI] [PubMed] [Google Scholar]
- Aoki H., Izumo S., Sadoshima J. Angiotensin II activates RhoA in cardiac myocytes: a critical role of RhoA in angiotensin II-induced premyofibril formation. Circ Res. 1998 Apr 6;82(6):666–676. doi: 10.1161/01.res.82.6.666. [DOI] [PubMed] [Google Scholar]
- Bogoyevitch M. A., Gillespie-Brown J., Ketterman A. J., Fuller S. J., Ben-Levy R., Ashworth A., Marshall C. J., Sugden P. H. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res. 1996 Aug;79(2):162–173. doi: 10.1161/01.res.79.2.162. [DOI] [PubMed] [Google Scholar]
- Bogoyevitch M. A., Glennon P. E., Andersson M. B., Clerk A., Lazou A., Marshall C. J., Parker P. J., Sugden P. H. Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes. The potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy. J Biol Chem. 1994 Jan 14;269(2):1110–1119. [PubMed] [Google Scholar]
- Bogoyevitch M. A., Glennon P. E., Sugden P. H. Endothelin-1, phorbol esters and phenylephrine stimulate MAP kinase activities in ventricular cardiomyocytes. FEBS Lett. 1993 Feb 15;317(3):271–275. doi: 10.1016/0014-5793(93)81291-7. [DOI] [PubMed] [Google Scholar]
- Bogoyevitch M. A., Ketterman A. J., Sugden P. H. Cellular stresses differentially activate c-Jun N-terminal protein kinases and extracellular signal-regulated protein kinases in cultured ventricular myocytes. J Biol Chem. 1995 Dec 15;270(50):29710–29717. doi: 10.1074/jbc.270.50.29710. [DOI] [PubMed] [Google Scholar]
- Choukroun G., Hajjar R., Fry S., del Monte F., Haq S., Guerrero J. L., Picard M., Rosenzweig A., Force T. Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH(2)-terminal kinases. J Clin Invest. 1999 Aug;104(4):391–398. doi: 10.1172/JCI6350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Choukroun G., Hajjar R., Kyriakis J. M., Bonventre J. V., Rosenzweig A., Force T. Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy. J Clin Invest. 1998 Oct 1;102(7):1311–1320. doi: 10.1172/JCI3512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clerk A., Bogoyevitch M. A., Anderson M. B., Sugden P. H. Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. J Biol Chem. 1994 Dec 30;269(52):32848–32857. [PubMed] [Google Scholar]
- Clerk A., Michael A., Sugden P. H. Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists, endothelin-1 and phenylephrine: a role in cardiac myocyte hypertrophy? J Cell Biol. 1998 Jul 27;142(2):523–535. doi: 10.1083/jcb.142.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clerk A., Sugden P. H. The p38-MAPK inhibitor, SB203580, inhibits cardiac stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs). FEBS Lett. 1998 Apr 10;426(1):93–96. doi: 10.1016/s0014-5793(98)00324-x. [DOI] [PubMed] [Google Scholar]
- Force T., Pombo C. M., Avruch J. A., Bonventre J. V., Kyriakis J. M. Stress-activated protein kinases in cardiovascular disease. Circ Res. 1996 Jun;78(6):947–953. doi: 10.1161/01.res.78.6.947. [DOI] [PubMed] [Google Scholar]
- Gille H., Kortenjann M., Thomae O., Moomaw C., Slaughter C., Cobb M. H., Shaw P. E. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J. 1995 Mar 1;14(5):951–962. doi: 10.1002/j.1460-2075.1995.tb07076.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gille H., Strahl T., Shaw P. E. Activation of ternary complex factor Elk-1 by stress-activated protein kinases. Curr Biol. 1995 Oct 1;5(10):1191–1200. doi: 10.1016/s0960-9822(95)00235-1. [DOI] [PubMed] [Google Scholar]
- Gillespie-Brown J., Fuller S. J., Bogoyevitch M. A., Cowley S., Sugden P. H. The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiomyocytes. J Biol Chem. 1995 Nov 24;270(47):28092–28096. doi: 10.1074/jbc.270.47.28092. [DOI] [PubMed] [Google Scholar]
- Glennon P. E., Kaddoura S., Sale E. M., Sale G. J., Fuller S. J., Sugden P. H. Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ Res. 1996 Jun;78(6):954–961. doi: 10.1161/01.res.78.6.954. [DOI] [PubMed] [Google Scholar]
- Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
- King A. J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., Marshall M. S. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature. 1998 Nov 12;396(6707):180–183. doi: 10.1038/24184. [DOI] [PubMed] [Google Scholar]
- Knowlton K. U., Baracchini E., Ross R. S., Harris A. N., Henderson S. A., Evans S. M., Glembotski C. C., Chien K. R. Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression. J Biol Chem. 1991 Apr 25;266(12):7759–7768. [PubMed] [Google Scholar]
- Knowlton K. U., Rockman H. A., Itani M., Vovan A., Seidman C. E., Chien K. R. Divergent pathways mediate the induction of ANF transgenes in neonatal and hypertrophic ventricular myocardium. J Clin Invest. 1995 Sep;96(3):1311–1318. doi: 10.1172/JCI118166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kudoh S., Komuro I., Mizuno T., Yamazaki T., Zou Y., Shiojima I., Takekoshi N., Yazaki Y. Angiotensin II stimulates c-Jun NH2-terminal kinase in cultured cardiac myocytes of neonatal rats. Circ Res. 1997 Jan;80(1):139–146. doi: 10.1161/01.res.80.1.139. [DOI] [PubMed] [Google Scholar]
- LaMorte V. J., Thorburn J., Absher D., Spiegel A., Brown J. H., Chien K. R., Feramisco J. R., Knowlton K. U. Gq- and ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following alpha 1-adrenergic stimulation. J Biol Chem. 1994 May 6;269(18):13490–13496. [PubMed] [Google Scholar]
- Li X., Lee J. W., Graves L. M., Earp H. S. Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway. EMBO J. 1998 May 1;17(9):2574–2583. doi: 10.1093/emboj/17.9.2574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mansour S. J., Matten W. T., Hermann A. S., Candia J. M., Rong S., Fukasawa K., Vande Woude G. F., Ahn N. G. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994 Aug 12;265(5174):966–970. doi: 10.1126/science.8052857. [DOI] [PubMed] [Google Scholar]
- Mason C. S., Springer C. J., Cooper R. G., Superti-Furga G., Marshall C. J., Marais R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 1999 Apr 15;18(8):2137–2148. doi: 10.1093/emboj/18.8.2137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McWhinney C. D., Hunt R. A., Conrad K. M., Dostal D. E., Baker K. M. The type I angiotensin II receptor couples to Stat1 and Stat3 activation through Jak2 kinase in neonatal rat cardiac myocytes. J Mol Cell Cardiol. 1997 Sep;29(9):2513–2524. doi: 10.1006/jmcc.1997.0489. [DOI] [PubMed] [Google Scholar]
- Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
- Nemoto S., Sheng Z., Lin A. Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy. Mol Cell Biol. 1998 Jun;18(6):3518–3526. doi: 10.1128/mcb.18.6.3518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pagès G., Lenormand P., L'Allemain G., Chambard J. C., Meloche S., Pouysségur J. Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8319–8323. doi: 10.1073/pnas.90.18.8319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Post G. R., Goldstein D., Thuerauf D. J., Glembotski C. C., Brown J. H. Dissociation of p44 and p42 mitogen-activated protein kinase activation from receptor-induced hypertrophy in neonatal rat ventricular myocytes. J Biol Chem. 1996 Apr 5;271(14):8452–8457. doi: 10.1074/jbc.271.14.8452. [DOI] [PubMed] [Google Scholar]
- Ramirez M. T., Sah V. P., Zhao X. L., Hunter J. J., Chien K. R., Brown J. H. The MEKK-JNK pathway is stimulated by alpha1-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy. J Biol Chem. 1997 May 30;272(22):14057–14061. doi: 10.1074/jbc.272.22.14057. [DOI] [PubMed] [Google Scholar]
- Sadoshima J., Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 1993 Apr;12(4):1681–1692. doi: 10.1002/j.1460-2075.1993.tb05813.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sadoshima J., Izumo S. Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993 Sep;73(3):413–423. doi: 10.1161/01.res.73.3.413. [DOI] [PubMed] [Google Scholar]
- Sadoshima J., Izumo S. Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ Res. 1995 Dec;77(6):1040–1052. doi: 10.1161/01.res.77.6.1040. [DOI] [PubMed] [Google Scholar]
- Sadoshima J., Izumo S. Signal transduction pathways of angiotensin II--induced c-fos gene expression in cardiac myocytes in vitro. Roles of phospholipid-derived second messengers. Circ Res. 1993 Sep;73(3):424–438. doi: 10.1161/01.res.73.3.424. [DOI] [PubMed] [Google Scholar]
- Sadoshima J., Izumo S. The heterotrimeric G q protein-coupled angiotensin II receptor activates p21 ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes. EMBO J. 1996 Feb 15;15(4):775–787. [PMC free article] [PubMed] [Google Scholar]
- Sadoshima J., Jahn L., Takahashi T., Kulik T. J., Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem. 1992 May 25;267(15):10551–10560. [PubMed] [Google Scholar]
- Sadoshima J., Qiu Z., Morgan J. P., Izumo S. Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. The critical role of Ca(2+)-dependent signaling. Circ Res. 1995 Jan;76(1):1–15. doi: 10.1161/01.res.76.1.1. [DOI] [PubMed] [Google Scholar]
- Sadoshima J., Qiu Z., Morgan J. P., Izumo S. Tyrosine kinase activation is an immediate and essential step in hypotonic cell swelling-induced ERK activation and c-fos gene expression in cardiac myocytes. EMBO J. 1996 Oct 15;15(20):5535–5546. [PMC free article] [PubMed] [Google Scholar]
- Sadoshima J. Versatility of the angiotensin II type 1 receptor. Circ Res. 1998 Jun 29;82(12):1352–1355. doi: 10.1161/01.res.82.12.1352. [DOI] [PubMed] [Google Scholar]
- Seger R., Krebs E. G. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726–735. [PubMed] [Google Scholar]
- Sheng Z., Knowlton K., Chen J., Hoshijima M., Brown J. H., Chien K. R. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem. 1997 Feb 28;272(9):5783–5791. doi: 10.1074/jbc.272.9.5783. [DOI] [PubMed] [Google Scholar]
- Shubeita H. E., Martinson E. A., Van Bilsen M., Chien K. R., Brown J. H. Transcriptional activation of the cardiac myosin light chain 2 and atrial natriuretic factor genes by protein kinase C in neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1305–1309. doi: 10.1073/pnas.89.4.1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sugden P. H., Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res. 1998 Aug 24;83(4):345–352. doi: 10.1161/01.res.83.4.345. [DOI] [PubMed] [Google Scholar]
- Sugden P. H., Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal. 1997 Aug;9(5):337–351. doi: 10.1016/s0898-6568(96)00191-x. [DOI] [PubMed] [Google Scholar]
- Thorburn A., Thorburn J., Chen S. Y., Powers S., Shubeita H. E., Feramisco J. R., Chien K. R. HRas-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy. J Biol Chem. 1993 Jan 25;268(3):2244–2249. [PubMed] [Google Scholar]
- Thorburn J., Carlson M., Mansour S. J., Chien K. R., Ahn N. G., Thorburn A. Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase. Mol Biol Cell. 1995 Nov;6(11):1479–1490. doi: 10.1091/mbc.6.11.1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thorburn J., Frost J. A., Thorburn A. Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy. J Cell Biol. 1994 Sep;126(6):1565–1572. doi: 10.1083/jcb.126.6.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thorburn J., Xu S., Thorburn A. MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. EMBO J. 1997 Apr 15;16(8):1888–1900. doi: 10.1093/emboj/16.8.1888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tzivion G., Luo Z., Avruch J. A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature. 1998 Jul 2;394(6688):88–92. doi: 10.1038/27938. [DOI] [PubMed] [Google Scholar]
- Wang Y., Su B., Sah V. P., Brown J. H., Han J., Chien K. R. Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol Chem. 1998 Mar 6;273(10):5423–5426. doi: 10.1074/jbc.273.10.5423. [DOI] [PubMed] [Google Scholar]
- Whitmarsh A. J., Shore P., Sharrocks A. D., Davis R. J. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. doi: 10.1126/science.7618106. [DOI] [PubMed] [Google Scholar]
- Wollert K. C., Taga T., Saito M., Narazaki M., Kishimoto T., Glembotski C. C., Vernallis A. B., Heath J. K., Pennica D., Wood W. I. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways. J Biol Chem. 1996 Apr 19;271(16):9535–9545. doi: 10.1074/jbc.271.16.9535. [DOI] [PubMed] [Google Scholar]
- Yamazaki T., Tobe K., Hoh E., Maemura K., Kaida T., Komuro I., Tamemoto H., Kadowaki T., Nagai R., Yazaki Y. Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase in cultured rat cardiac myocytes. J Biol Chem. 1993 Jun 5;268(16):12069–12076. [PubMed] [Google Scholar]
- Yujiri T., Sather S., Fanger G. R., Johnson G. L. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science. 1998 Dec 4;282(5395):1911–1914. doi: 10.1126/science.282.5395.1911. [DOI] [PubMed] [Google Scholar]
- Zechner D., Thuerauf D. J., Hanford D. S., McDonough P. M., Glembotski C. C. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. J Cell Biol. 1997 Oct 6;139(1):115–127. doi: 10.1083/jcb.139.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zou Y., Komuro I., Yamazaki T., Aikawa R., Kudoh S., Shiojima I., Hiroi Y., Mizuno T., Yazaki Y. Protein kinase C, but not tyrosine kinases or Ras, plays a critical role in angiotensin II-induced activation of Raf-1 kinase and extracellular signal-regulated protein kinases in cardiac myocytes. J Biol Chem. 1996 Dec 27;271(52):33592–33597. doi: 10.1074/jbc.271.52.33592. [DOI] [PubMed] [Google Scholar]