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(Circulation Research. 1995;76:1-15.)
© 1995 American Heart Association, Inc.

Articles

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 Ca²⁺-Dependent Signaling

Junichi Sadoshima, Zhihua Qiu, James P. Morgan, Seigo Izumo

From the Cardiovascular Research Center, Division of Cardiology, University of Michigan Medical Center, Ann Arbor (J.S., S.I.), and the Cardiovascular Division, Beth Israel Hospital, and Department of Medicine, Harvard Medical School, Boston, Mass (J.S., Z.Q., J.P.M., S.I.).

Correspondence to Dr Seigo Izumo, Division of Cardiology, University of Michigan Medical Center, Ann Arbor, MI 48109-0644.

Abstract Many hypertrophic stimuli such as angiotensin II (Ang II) activate phospholipases through G protein–coupled receptors in cardiac myocytes. However, it is not known whether these stimuli also activate the tyrosine phosphorylation–dependent signaling pathway, which plays an essential role in growth factor–induced mitogenic responses in other cell types. Serine/threonine kinases such as mitogen-activated protein (MAP) kinases and 90-kD S6 kinase (RSK) are activated in response to many growth stimuli and are important downstream signaling pathways of tyrosine kinases. Therefore, we examined whether Ang II activates these protein kinases in primary cultures of cardiac myocytes and fibroblasts from neonatal rats. Ang II rapidly induced tyrosine phosphorylation of multiple proteins, including 42-, 44-, 75- to 80-, and 120- to 130-kD proteins, in both cardiac myocytes and fibroblasts. This was accompanied by an increase in tyrosine kinase activity. The 42- and 44-kD proteins were immunologically related to an extracellular signal-regulated kinase family (MAP kinases). Ang II rapidly increased kinase activity of MAP kinases and their downstream kinase, RSK. The Ang II–induced tyrosine phosphorylation and activation of MAP kinases and RSK were AT₁ receptor–mediated. Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate or an increase in intracellular Ca²⁺ by the Ca²⁺ ionophore A23187 was sufficient to cause tyrosine phosphorylation of multiple proteins and activation of MAP kinase and RSK. Although downregulation of PKC did not suppress Ang II–induced activation of MAP kinase and RSK, chelating intracellular Ca²⁺ by BAPTA-AM completely abolished Ang II–induced activation of these kinases. Activation of MAP kinases and RSK was also observed in myocytes stimulated with other agonists for G_q protein–coupled receptors, such as phenylephrine, norepinephrine, and endothelin 1, but not with agonists to G_s protein–coupled receptors, such as isoproterenol. These results suggest that Ang II and other hypertrophic stimuli, known to act through G_q protein–coupled receptors, rapidly cause tyrosine phosphorylation of several intracellular substrates through activation of tyrosine kinase and activate MAP kinases and RSK in cardiac myocytes as well as in cardiac fibroblasts. Furthermore, intracellular Ca²⁺, rather than PKC, seems to be critical for Ang II–induced activation of these protein kinases in cardiac myocytes.

Key Words: mitogen-activated protein kinase • 90-kD ribosomal S6 kinase • angiotensin II

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				C. Montessuit and A. Thorburn Transcriptional Activation of the Glucose Transporter GLUT1 in Ventricular Cardiac Myocytes by Hypertrophic Agonists J. Biol. Chem., March 26, 1999; 274(13): 9006 - 9012. [Abstract] [Full Text] [PDF]

				T. Shimizu, K.-i. Kinugawa, A. Yao, Y. Sugishita, K. Sugishita, K. Harada, H. Matsui, O. Kohmoto, T. Serizawa, and T. Takahashi Platelet-derived growth factor induces cellular growth in cultured chick ventricular myocytes Cardiovasc Res, March 1, 1999; 41(3): 641 - 653. [Abstract] [Full Text] [PDF]

				Z. Gao, T. Chen, M. J. Weber, and J. Linden A2B Adenosine and P2Y2 Receptors Stimulate Mitogen-activated Protein Kinase in Human Embryonic Kidney-293 Cells. CROSS-TALK BETWEEN CYCLIC AMP AND PROTEIN KINASE C PATHWAYS J. Biol. Chem., February 26, 1999; 274(9): 5972 - 5980. [Abstract] [Full Text] [PDF]

				J. A. Maloney, O. M. Tsygankova, L. Yang, Q. Li, A. Szot, K. Baysal, and J. R. Williamson Activation of ERK by Ca2+ store depletion in rat liver epithelial cells Am J Physiol Cell Physiol, January 1, 1999; 276(1): C221 - C230. [Abstract] [Full Text] [PDF]

				M. R. Rosen, I. S. Cohen, P. Danilo Jr., and S. F. Steinberg The heart remembers Cardiovasc Res, December 1, 1998; 40(3): 469 - 482. [Full Text] [PDF]

				J. M. Park, J. G. Borer, M. R. Freeman, and C. A. Peters Stretch activates heparin-binding EGF-like growth factor expression in bladder smooth muscle cells Am J Physiol Cell Physiol, November 1, 1998; 275(5): C1247 - C1254. [Abstract] [Full Text] [PDF]

				M. O. Gray, C. S. Long, J. E. Kalinyak, H.-T. Li, and J. S. Karliner Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-{beta}1 and endothelin-1 from fibroblasts Cardiovasc Res, November 1, 1998; 40(2): 352 - 363. [Abstract] [Full Text] [PDF]

				M. Yano, S. Kim, Y. Izumi, S. Yamanaka, and H. Iwao Differential Activation of Cardiac c-Jun Amino-Terminal Kinase and Extracellular Signal-Regulated Kinase in Angiotensin II–Mediated Hypertension Circ. Res., October 5, 1998; 83(7): 752 - 760. [Abstract] [Full Text] [PDF]

				A. Nagahara, L. Wang, J. Del Valle, and A. Todisco Regulation of c-Jun NH2-terminal kinases in isolated canine gastric parietal cells Am J Physiol Gastrointest Liver Physiol, October 1, 1998; 275(4): G740 - G748. [Abstract] [Full Text] [PDF]

				S. Murasawa, Y. Mori, Y. Nozawa, H. Masaki, K. Maruyama, Y. Tsutsumi, Y. Moriguchi, Y. Shibasaki, Y. Tanaka, T. Iwasaka, et al. Role of Calcium-Sensitive Tyrosine Kinase Pyk2/CAKß/RAFTK in Angiotensin II–Induced Ras/ERK Signaling Hypertension, October 1, 1998; 32(4): 668 - 675. [Abstract] [Full Text] [PDF]

				K.-D. Schluter, Y. Goldberg, G. Taimor, M. Schafer, and H. Michael Piper Role of phosphatidylinositol 3-kinase activation in the hypertrophic growth of adult ventricular cardiomyocytes Cardiovasc Res, October 1, 1998; 40(1): 174 - 181. [Abstract] [Full Text] [PDF]

				H. Kai, A. Muraishi, Y. Sugiu, H. Nishi, Y. Seki, F. Kuwahara, A. Kimura, H. Kato, and T. Imaizumi Expression of Proto-oncogenes and Gene Mutation of Sarcomeric Proteins in Patients With Hypertrophic Cardiomyopathy Circ. Res., September 21, 1998; 83(6): 594 - 601. [Abstract] [Full Text] [PDF]

				S. Kudoh, I. Komuro, Y. Hiroi, Y. Zou, K. Harada, T. Sugaya, N. Takekoshi, K. Murakami, T. Kadowaki, and Y. Yazaki Mechanical Stretch Induces Hypertrophic Responses in Cardiac Myocytes of Angiotensin II Type 1a Receptor Knockout Mice J. Biol. Chem., September 11, 1998; 273(37): 24037 - 24043. [Abstract] [Full Text] [PDF]

				S. M. Dodge, M. A. Beardslee, B. J. Darrow, K. G. Green, E. C. Beyer, and J. E. Saffitz Effects of angiotensin II on expression of the gap junction channel protein connexin43 in neonatal rat ventricular myocytes J. Am. Coll. Cardiol., September 1, 1998; 32(3): 800 - 807. [Abstract] [Full Text] [PDF]

				K. McBride and M. Nemer The C-Terminal Domain of c-fos Is Required for Activation of an AP-1 Site Specific for jun-fos Heterodimers Mol. Cell. Biol., September 1, 1998; 18(9): 5073 - 5081. [Abstract] [Full Text]

				A. Goussev, V. G. Sharov, H. Shimoyama, M. Tanimura, M. Lesch, S. Goldstein, and H. N. Sabbah Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure Am J Physiol Heart Circ Physiol, August 1, 1998; 275(2): H626 - H631. [Abstract] [Full Text] [PDF]

				J. W. Adams, V. P. Sah, S. A. Henderson, and J. H. Brown Tyrosine Kinase and c-Jun NH2-Terminal Kinase Mediate Hypertrophic Responses to Prostaglandin F2{alpha} in Cultured Neonatal Rat Ventricular Myocytes Circ. Res., July 27, 1998; 83(2): 167 - 178. [Abstract] [Full Text] [PDF]

				S. J. Fuller, J. Gillespie-Brown, and P. H. Sugden Oncogenic src, raf, and ras Stimulate a Hypertrophic Pattern of Gene Expression and Increase Cell Size in Neonatal Rat Ventricular Myocytes J. Biol. Chem., July 17, 1998; 273(29): 18146 - 18152. [Abstract] [Full Text] [PDF]

				N. O. Dulin, L. D. Alexander, S. Harwalkar, J. R. Falck, and J. G. Douglas Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin II PNAS, July 7, 1998; 95(14): 8098 - 8102. [Abstract] [Full Text] [PDF]

				R. S. Ross, C. Pham, S.-Y. Shai, J. I. Goldhaber, C. Fenczik, C. C. Glembotski, M. H. Ginsberg, and J. C. Loftus ß1 Integrins Participate in the Hypertrophic Response of Rat Ventricular Myocytes Circ. Res., June 15, 1998; 82(11): 1160 - 1172. [Abstract] [Full Text] [PDF]

				P. Kometiani, J. Li, L. Gnudi, B. B. Kahn, A. Askari, and Z. Xie Multiple Signal Transduction Pathways Link Na+/K+-ATPase to Growth-related Genes in Cardiac Myocytes. THE ROLES OF Ras AND MITOGEN-ACTIVATED PROTEIN KINASES J. Biol. Chem., June 12, 1998; 273(24): 15249 - 15256. [Abstract] [Full Text] [PDF]

				S. McKay, J. C. de Jongste, P. R. Saxena, and H. S. Sharma Angiotensin II Induces Hypertrophy of Human Airway Smooth Muscle Cells: Expression of Transcription Factors and Transforming Growth Factor-beta 1 Am. J. Respir. Cell Mol. Biol., June 1, 1998; 18(6): 823 - 833. [Abstract] [Full Text]

				S. T Rapundalo Cardiac protein phosphorylation: functional and pathophysiological correlates Cardiovasc Res, June 1, 1998; 38(3): 559 - 588. [Abstract] [Full Text] [PDF]