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J Biol Chem, Vol. 273, Issue 10, 5423-5426, March 6, 1998

COMMUNICATION
Cardiac Hypertrophy Induced by Mitogen-activated Protein Kinase Kinase 7, a Specific Activator for c-Jun NH₂-terminal Kinase in Ventricular Muscle Cells^*

Yibin Wang, Bing Su^§, Valerie P. Sah^¶, Joan Heller Brown^¶, Jiahuai Han, and Kenneth R. Chien^**

From the Departments of  Medicine and ^¶ Pharmacology, University of California at San Diego, La Jolla, California 92093, the ^§ Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and the  Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

	ABSTRACT

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Activation of stress-activated protein kinases, including the p38 and the c-Jun NH₂-terminal kinases (JNK), have been associated with the onset of cardiac hypertrophy and cell death in response to hemodynamic overload and ischemia/reperfusion injury. Upon infection of cultured neonatal rat cardiac myocytes with recombinant adenoviral vectors expressing a wild type and a constitutively active mutant of MKK7 (or JNKK2), JNK was specifically activated without affecting other mitogen-activated protein kinases, including extracellular signal-regulated protein kinases and p38. Specific activation of the JNK pathway in cardiac myocytes induced characteristic features of hypertrophy, including an increase in cell size, elevated expression of atrial natriuretic factor, and induction of sarcomere organization. In contrast, co-activation of both JNK (by MKK7) and p38 (by MKK3 or MKK6) in cardiomyocytes led to an induction of cytopathic responses and suppression of hypertrophic responses. These data provide the first direct evidence that activation of JNK alone is sufficient to induce characteristic features of cardiac hypertrophy, thereby supporting an active role for the JNK pathway in the development of cardiac hypertrophy. The cytopathic response, as a result of co-activation of both JNK and p38, may contribute to the loss of contractile function and viability of cardiomyocytes following hemodynamic overload and cardiac ischemia/reperfusion injury.

	INTRODUCTION

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Cardiac hypertrophy and heart failure are multi-step pathophysiological processes involving extracellular stimuli, such as mechanical stress, cytokines and growth factors, and intracellular signaling pathways, including mitogen-activated protein (MAP)¹ kinase pathways (1-5). The MAP kinase signaling pathways consist of three major phosphorylation cascades, i.e. the extracellular signal-regulated protein kinases (ERK), the c-Jun NH₂-terminal kinases (JNK), and the p38 MAP kinases (6, 7). JNK and p38 pathways are collectively termed stress-activated protein kinases because they are activated by various stress-related stimuli (8). It has been shown that p38 MAP kinase activity is activated in hypertrophied² and ischemic hearts (10, 11). In neonatal cardiomyocytes, activation of the p38 pathway by an upstream activator MKK6 induces characteristic features of hypertrophy (12, 13). In contrast, activation of p38 activity by another upstream activator, MKK3, gives rise to the mixed responses of hypertrophy and apoptosis, possibly mediated by different p38 isoforms (12). These studies support the hypothesis that p38 may mediate the hypertrophic process in vivo and contribute to the myocyte apoptosis that is observed in post-ischemic hearts as well as end stage failing hearts (14).

JNK is the first MAP kinase that is activated in mouse heart by pressure-overload,³ and is also activated in Ras induced hypertrophied transgenic hearts (15). JNK activation is also associated with ischemia/reperfusion (10, 11). It can be induced by an -adrenergic agonist, phenylephrine (PE), and is required for the induction of atrial natriuretic factor (ANF) promoter activity by PE in cardiac myocytes (15). In a separate study, activated MEKK-1, an upstream activator of JNK, has been shown to be able to activate some of the characteristic features of hypertrophy in neonatal cardiomyocytes (13). However, because PE treatment and the activated MEKK-1 also activate other MAP kinases, including ERK and p38, the specific function of JNK in cardiac hypertrophy is still not yet clear. Recently, several groups have reported the cloning of a new MAP kinase kinase, MKK7 (also named JNKK-2), which is able to specifically activate the JNK pathway without affecting ERK and p38 activities (16-18).⁴ In this study, we examine the effects of MKK7-mediated JNK activation on neonatal cardiac myocytes. Our results show that specific activation of the JNK pathway in cardiac myocytes is sufficient to induce characteristic features of hypertrophy. Furthermore, co-activation of JNK and p38 pathways in cardiac myocytes leads to cytopathic responses in cardiac myocytes and induction of cell death. These results support the hypothesis that both JNK and p38 play pivotal roles in the development of cardiac hypertrophy and that combined effects of JNK and p38 may contribute to the pathophysiological process of heart failure.

	EXPERIMENTAL PROCEDURES

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Culture of Neonatal Rat Cardiac Myocytes-- Ventricular myocytes from 1-2-day-old Sprague-Dawley rats were prepared using a Percoll gradient method as described previously (19). The cells were plated in serum containing media (4:1 Dulbecco's modified Eagle's medium: medium 199, 10% horse serum, 5% fetal bovine serum, 100 units/ml penicillin, 100 mg/ml streptomycin, and 10 mM glutamine) overnight and changed into serum-free media when they were infected with adenoviruses at a multiplicity of infection of 50-100 particles/cell for 16 h. The cells were then cultured for an additional 36 h before morphological or biochemical analysis.

Molecular Cloning of Human MKK7 cDNA-- Degenerated oligonucleotides, ATHATHGCNGTNAARCAR and TTNACRTCNCKRTGDAT, that correspond to the conserved kinase subdomain II and VI of Drosophila MAPKK hep were used to amplify a MAPKK-specific cDNA fragment from first-strand cDNA synthesized with HeLa cell poly(A)⁺ mRNA by polymerase chain reaction. One DNA sequence from the polymerase chain reaction product was found to be homologous to both hep and human JNKK1. This DNA fragment was used to screen a human B-cell library (Invitrogen). The full-length MKK7 cDNA was constructed from a cDNA clone with the longest coding sequence and a cDNA clone from the expressed sequence tag gene bank (accession number H85962) that has overlapping sequences.

Recombinant Adenovirus Vectors-- Recombinant adenoviruses expressing green fluorescent protein (Adv/GFP) and activated mutants of MKK6 and MKK3 (Adv/MKK6bE and Adv/MKK3bE) have been described elsewhere (12, 20). Recombinant adenoviruses expressing wild type and activated mutant (Ser²⁷¹ and Thr²⁷⁵ to Asp) of human MKK7 gene were generated by homologous recombination between the plasmid pJM17 and shuttle plasmids with MKK7 cDNAs cloned into the HindIII and XbaI sites of the pAdv/RSV vector (20). The concentrated recombinant adenoviruses were prepared and titered as described (21).

MAP Kinase Assays-- Protein extracts from myocytes were prepared and assayed for kinase activities as described previously (12). The MAP kinases were immunoprecipitated using rabbit polyclonal anti-JNK1, -p38, or -ERK1 antibodies (Santa Cruz Biotechnology, Inc.) conjugated to protein A-Sepharose. The kinase assays were performed at 30 °C using [-³²P]ATP and myelin basic protein (Sigma) as a substrate for ERK1 and p38 or using GST-c-Jun (1-79) as a substrate for JNK. The phosphorylated substrate was separated by SDS-polyacrylamide gel electrophoresis and visualized by autoradiography. The incorporated ³²P_i in the substrate was quantified by radioanalytic scanning (AMBIS).

Immunohistochemical Assay-- Immunohistochemical analysis of adenovirus-infected cardiac myocytes were performed as described (12). The expression of the ANF protein was detected using rabbit anti-rat -ANF polyclonal antibody (Peninsula) and fluorescein isothiocyanate-conjugated goat anti-rabbit secondary antibody (Amersham). The sarcomere structure was detected using rhodamine-conjugated phalloidin (Sigma).

	RESULTS

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Specific Activation of JNK by MKK7 in Cardiac Myocytes-- To study the specific function of the JNK pathway in cultured cardiac myocytes, recombinant adenoviruses expressing wild type (Adv/MKK7wt) or activated mutant of MKK7 (Adv/MKK7D) were generated as described under "Experimental Procedures." Approximately 5 × 10⁵ rat neonatal cardiac myocytes were infected with 2.5-5 × 10⁷ viral particles of different vectors as described. In our previous study, it has been shown that at this dosage, more than 95% of the cardiac myocytes are infected by the adenoviral vector and express the transgene product (12). MAP kinase activities were measured from cells 48 h after infection. As shown in Fig. 1, JNK activity was significantly activated up to 4-fold in cells infected with Adv/MKK7wt and Adv/MKK7D but remained at basal levels in cells that were treated with a control Adv vector expressing GFP (control). In contrast, the ERK and the p38 basal level activities were not significantly altered (Fig. 1b). These data indicate that either wild type or activated MKK7 functions as a JNK-specific activator in cardiac myocytes in the same fashion as demonstrated in other cell types (16-18).⁴

View larger version (31K): [in this window] [in a new window]   Fig. 1.   Specific activation of JNK activity by MKK7 in cardiac myocytes. Cultured cardiac myocytes were infected with adenovirus expressing GFP (Control), wild type MKK7 (MKK7wt), and activated MKK7 mutant (MKK7D) as described under "Experimental Procedures." a, kinase activities of JNK, ERK, and p38 were measured from 5 × 105 infected cardiac myocytes as described (12). b, relative kinase activities are presented as fold of activation ± S.E. from two independent experiments. The increases in JNK activity with MKK7wt and MKK7D are significant (p < 0.01, Student's t test).

MKK7 Induces Characteristic Features of Hypertrophy in Cardiac Myocytes-- To characterize the functional effects of JNK activation on cardiac myocytes, we examined the morphological and biochemical features of the muscle cells that were infected with Adv/MKK7wt and Adv/MKK7D in comparison with untreated cells or cells treated with a control vector. Overexpression of a wild type or an activated mutant of the MKK7 resulted in a hypertrophic change in morphology (Fig. 2a) and a significant increase in cell size (Fig. 2b). By immunohistochemical analysis using antibodies specifically against ANF protein, we demonstrated that this hypertrophic marker gene was significantly induced in almost all cardiac myocytes that were infected with Adv/MKK7wt or Adv/MKK7D (f and h in Fig. 3) but not in untreated myocytes or cells that were infected with a control Adv/GFP vector (b and d in Fig. 3). Finally, we have also analyzed the cytoskeletal organization in cardiac myocytes by phalloidin staining. As shown in Fig. 3, expression of MKK7 significantly induced the organization of sarcomere structure (e and g in Fig. 3) as compared with untreated cells and cells infected with the control vector (a and c in Fig. 3). These data clearly demonstrated that specific activation of the JNK pathway by MKK7 can induce characteristic features of cardiac hypertrophy in cultured myocytes.

View larger version (53K): [in this window] [in a new window]   Fig. 2.   Activation of JNK activity in cardiac myocytes induced hypertrophy. a, cells infected with no virus (Control) and with adenoviruses expressing GFP (Adv/GFP), wild type MKK7 (Adv/MKK7wt), and activated mutant of MKK7 (Adv/MKK7D) were examined under light microscopy. b, the cell surface area was analyzed using NIH Image software. The values represent the mean surface area ± S.E. from 20 measurements in each group. The increases in cell surface area from MKK7wt and MKK7D groups are highly significant (p < 0.0001, Student's t test).

View larger version (92K): [in this window] [in a new window]   Fig. 3.   Activation of JNK pathway induced ANF expression and organization of sarcomere structure in cardiac myocytes. Cardiac myocytes were infected with no virus (Untreated, a and b) or vectors expressing LacZ (Adv/LacZ, c and d), wild type MKK7 (Adv/MKK7wt, e and f), or activated MKK7 (Adv/MKK7D, g and h) as described under "Experimental Procedures." Cells were stained for F-actin using rhodamine-conjugated phalloidin (a, c, e, and g) and for ANF protein using rabbit polyclonal anti-ANF antibodies (b, f, d, and h). Induction of ANF expression was identified from positive perinuclear staining of ANF protein (f and h).

Cytopathic Response and Cell Death Induced by Co-activation of the JNK and p38 Pathways-- JNK appears to be co-activated with p38 in vivo under different physiological stresses, such as pressure-overload³ and ischemia/reperfusion (10, 11). They are also co-activated in transgenic mouse hearts expressing activated Ras (15).² To characterize the combined effects of both JNK and p38 pathways, upstream activators for both JNK and p38 pathways were co-expressed in cardiac muscle cells. In our previous study (12), it has been demonstrated that overexpression of a p38-specific activator, MKK6bE, is able to induce significant hypertrophy, whereas overexpression of MKK3bE, another p38-specific activator, induced mixed responses of hypertrophy and apoptosis (a and c of Fig. 4). When MKK6bE and MKK7D were co-expressed in cardiac myocytes, however, the hypertrophic response observed in either MKK6bE- or MKK7D-expressing cells was significantly inhibited (d of Fig. 4). The cells displayed a cytopathic phenotype characterized by the appearance of many vacuoles in the cytoplasm before death. Overexpression of MKK7D and MKK3bE also induce significant cell death and cytopathic responses in the living cells (e of Fig. 4). These data suggest that co-activation of JNK and p38 pathways resulted in the induction of a cytopathic response and cell death.

View larger version (137K): [in this window] [in a new window]   Fig. 4.   Co-activation of JNK and p38 pathways led to suppression of hypertrophy and induction of cytopathic response and cell death. Cardiac myocytes were either infected with viral vectors expressing MKK6bE (a), MKK7D (b), or MKK3bE (c) alone or co-infected with vectors expressing MKK6bE and MKK7D (d) or MKK3bE and MKK7D (e). The cellular morphology was examined and photographed under light microscopy.

	DISCUSSION

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In this report, we have analyzed the direct effects of JNK activation in cardiac myocytes by overexpressing a specific upstream activator, MKK7 using recombinant adenovirus-mediated gene transfer. We have shown that wild type and activated MKK7 specifically activate JNK activity without affecting ERK and p38 activities. Specific activation of JNK in cardiac myocytes induced a hypertrophic response characterized by an increase in cell size, the induction of ANF expression, and enhanced organization of sarcomere structure. This result suggests that specific activation of JNK is sufficient to initiate a hypertrophic response in cardiomyocytes. However, we cannot rule out the involvement of p38 in such a response because there are still significant p38 basal level activities in the cultured cardiac myocytes (Fig. 1). Co-activation of JNK and p38 in cardiac myocytes, however, failed to synergize in their hypertrophic effects. Instead, this led to induction of cytopathic responses and cell death.

JNK activity is quickly activated by pressure-overload in transverse aortic constriction treated animals followed by activation of p38 at a later time point.³ Combined with the results from this study, a model can be hypothesized where the activation of JNK may contribute directly to the development of hypertrophy at the earlier time points of pressure overload. In the setting of long term hemodynamic stress, both JNK and p38 activities are activated that lead to dysfunction and death of the myocytes. This hypothesis needs to be tested in vivo by creating transgenic animals with altered stress-activated protein kinases activities in heart and studying their effects on cardiac functions using miniaturized physiological technology (9).

	ACKNOWLEDGEMENT

We thank Mahmoud Itani for excellent technical assistance.

	FOOTNOTES

^* This work was supported in part by grants from the American Heart Association and National Institutes of Health (to K. R. C.), by American Heart Association Grant-in-Aid 95007690 and National Institutes of Health Grants GM51417 and AI41637 (to J. H.), and by National Institutes of Health Grants HL28143 and HL46345 (to J. H. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Medicine and Center for Molecular Genetics, Mail Box 0613-C, 9500 Gilman Dr., University of California at San Diego, La Jolla, CA 92093. Tel.: 619-534-4801; Fax: 619-534-8081; E-mail: kchien{at}ucsd.edu.

¹ The abbreviations used are: MAP, mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun NH₂-terminal kinase; PE, phenylephrine; ANF, atrial natriuretic factor; Adv, adenovirus; GFP, green fluorescent protein.

² J. J. Hunter, M. Shimizu, J. Brown, V. P. Sah, K. Gottshall, C. Milano, R. Lefkowiz, J. H. Brown, and K. R. Chien, submitted for publication.

³ P. V. Sah and J. H. Brown, unpublished results.

⁴ J. Yang, L. New, Y. Jiang, J. Han, and B. Su, unpublished results.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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				E. van Rooij, P. A. Doevendans, C. C. de Theije, F. A. Babiker, J. D. Molkentin, and L. J. De Windt Requirement of Nuclear Factor of Activated T-cells in Calcineurin-mediated Cardiomyocyte Hypertrophy J. Biol. Chem., December 6, 2002; 277(50): 48617 - 48626. [Abstract] [Full Text] [PDF]

				S.-K. Leivonen, A. Chantry, L. Hakkinen, J. Han, and V.-M. Kahari Smad3 Mediates Transforming Growth Factor-beta -induced Collagenase-3 (Matrix Metalloproteinase-13) Expression in Human Gingival Fibroblasts. EVIDENCE FOR CROSS-TALK BETWEEN Smad3 AND p38 SIGNALING PATHWAYS J. Biol. Chem., November 22, 2002; 277(48): 46338 - 46346. [Abstract] [Full Text] [PDF]

				L. Pianese, L. Busino, I. De Biase, T. de Cristofaro, M. S. Lo Casale, P. Giuliano, A. Monticelli, M. Turano, C. Criscuolo, A. Filla, et al. Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells Hum. Mol. Genet., November 1, 2002; 11(23): 2989 - 2996. [Abstract] [Full Text] [PDF]

				B. G. Petrich, X. Gong, D. L. Lerner, X. Wang, J. H. Brown, J. E. Saffitz, and Y. Wang c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes Circ. Res., October 4, 2002; 91(7): 640 - 647. [Abstract] [Full Text] [PDF]

				T. Efimova, A. Deucher, T. Kuroki, M. Ohba, and R. L. Eckert Novel Protein Kinase C Isoforms Regulate Human Keratinocyte Differentiation by Activating a p38delta Mitogen-activated Protein Kinase Cascade That Targets CCAAT/Enhancer-binding Protein alpha J. Biol. Chem., August 23, 2002; 277(35): 31753 - 31760. [Abstract] [Full Text] [PDF]

				N. Reunanen, S.-P. Li, M. Ahonen, M. Foschi, J. Han, and V.-M. Kahari Activation of p38alpha MAPK Enhances Collagenase-1 (Matrix Metalloproteinase (MMP)-1) and Stromelysin-1 (MMP-3) Expression by mRNA Stabilization J. Biol. Chem., August 23, 2002; 277(35): 32360 - 32368. [Abstract] [Full Text] [PDF]

				M. Sotoudeh, Y.-S. Li, N. Yajima, C.-C. Chang, T.-C. Tsou, Y. Wang, S. Usami, A. Ratcliffe, S. Chien, and J. Y.-J. Shyy Induction of apoptosis in vascular smooth muscle cells by mechanical stretch Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1709 - H1716. [Abstract] [Full Text] [PDF]

				S. Hirotani, K. Otsu, K. Nishida, Y. Higuchi, T. Morita, H. Nakayama, O. Yamaguchi, T. Mano, Y. Matsumura, H. Ueno, et al. Involvement of Nuclear Factor-{kappa}B and Apoptosis Signal-Regulating Kinase 1 in G-Protein-Coupled Receptor Agonist-Induced Cardiomyocyte Hypertrophy Circulation, January 29, 2002; 105(4): 509 - 515. [Abstract] [Full Text] [PDF]

				C. L. Antos, T. A. McKinsey, N. Frey, W. Kutschke, J. McAnally, J. M. Shelton, J. A. Richardson, J. A. Hill, and E. N. Olson Activated glycogen synthase-3beta suppresses cardiac hypertrophy in vivo PNAS, January 7, 2002; (2002) 231619298. [Abstract] [Full Text] [PDF]

T. Omura, M. Yoshiyama, K. Yoshida, Y. Nakamura, S. Kim, H. Iwao, K. Takeuchi, and J. Yoshikawa Dominant Negative Mutant of c-Jun Inhibits Cardiomyocyte Hypertrophy Induced by Endothelin 1 and Phenylephrine Hypertension, January 1, 2002; 39(1): 81 - 86. [Abstract] [Full Text] [PDF]