The effect of angiotensin II on mitogen-activated protein kinase in human cardiomyocytes

Abstract

The role of angiotensin II (Ang II)-receptors on mitogen-activated protein kinase (MAPK) activation in cardiomyocytes remains controversial. Therefore, the current study was designed to investigate the actions of AT₁- and AT₂-receptors on Ang II-induced extracellular signal-regulated kinase (ERK), p38 and the c-Jun N-terminal kinase (JNK) MAPK activities in human cardiomyocytes. Human cardiac tissue was obtained from open-heart surgery (n=6). The cardiac tissue was minced and incubated in the special tissue culture system for 24 hours in the absence or presence of Ang II (10^-7 M). These studies were repeated with the AT₁-receptor antagonist losartan (10^-6 M) or the AT₂-receptor antagonist PD-123319 (10^-6 M). Immunohistochemical staining and Western blot analysis with phospho-antibodies were performed to determine ERK, JNK and p38 activities. Ang II increased ERK and p38 activities in human cardiomyocytes. The effects of Ang II were abolished by losartan and enhanced by PD-123319. Co-incubation with both losartan and PD-123319 resulted in a decrease of ERK and p38 activities in cardiomyocytes. The immunohistochemical staining of JNK showed no significant differences between Ang II alone, Ang II plus losartan and Ang II plus PD-123319 groups. In conclusion, Ang II has a potent effect on ERK and p38 MAPK activities in cardiomyocytes, by acting through AT₁-receptors. This effect of Ang II is modified by AT₂-receptors. Therefore, Ang II, via AT₁- and AT₂-receptor stimulation, has a distinct effect on MAPK activity in cardiomyocytes.

Keywords

angiotensin II AT1- and AT2-receptors MAPK ERK p38 JNK

Get full access to this article

View all access options for this article.

References

Baker KM , Booz GW , Dostal DE Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol 1992;54:227-41.

Schunkert H. , Dzau VJ , Tang SS , Hirsh AT , Apstein CS , Lorell BH Increased rat cardiac angiotensin-converting enzyme and mRNA expression in pressure overload ventricular hypertrophy: effects on coronary resistance, contractility and relaxation. Annu Rev Physiol 1990;86:1913-20.

Suzuki J. , Matsubara H. , Inada M. Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy. Circ Res 1993;73:439-47.

Lopez JJ , Lorell BH , Ingelfinger JR et al. Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts.AmJPhysiol 1994;267:H844-H852.

Lee Y. -A, Liang C. -S, Lee M. - A. Lindpainter K. Local stress, not systemic factors, regulate gene expression of the cardiac renin-angiotensin system in vivo: a comprehensive study of all its components in the dog. Proc Natl Acad Sci USA 1996;93: 11035-40.

Nio Y. , Matsubara H. , Murasawa S. , Kanasaki M. , Inada M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest 1995 ;95:46-54.

Meggs LG , Coupet J. , Huang H. et al. Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats. Circ Res 1993;72:1149-62.

Everett AD , Tufro-McReddie A. , Fischer A. , Gomez RA Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-b1 expression. Hypertension 1994;23:587-92.

Sechi LA , Griffin CA , Grady EF , Kalinyak JE , Schambelan M. Characterization of angiotensin II receptor in rat heart. Circ Res 1992;71:1482-9.

10.

Timmermans Pbmwm , Wong RC , Chiu AT Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45:205-51.

11.

Horiuchi M. , Hayashida W. , Kambe T. , Yamada T. , Dzau VJ Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis.JBiol Chem 1997;272:19022-6.

12.

Masaki H. , Kurihara I. , Yamaki A. et al. Cardiac-specific over-expression of angiotensin II, AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.JClin Invest 1998;101:527-35.

13.

Zhang J. , Pratt RE The AT2 receptor selectively associates with Giα2 and Giα3 in the rat fetus. J Biol Chem 1996;271:15026-33.

14.

Nakajima M. , Hutchinson HG , Fuginaga M. et al. The angiotensin II type 2 (AT2) antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci USA 1995;82:10663-7.

15.

Yamada T. , Toriuchi M. , Dzau VJ Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA 1996;93:156-60.

16.

Huang XC , Richards EM , Sumners C. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptor and inhibited by angiotensin II type 2 receptors . J Biol Chem 1996;271:15635-41.

17.

Seger R. , Krebs EG The MAPK signaling cascade. FASEB J 1995;9:726-35.

18.

Force T. , Bonventre JV Growth factors and mitogen-activated protein kinases. Hypertension 1998;31(pt 2):152-61.

19.

Davis RJ MAPKs: new JNK expands the group. Trends Biochem Sci 1994;19:470-3.

20.

Kyriakis JM , Woodgett JR , Avruch J. The stress-activated protein kinases. Ann NY Acad Sci 1995;766:303-19.

21.

Abe J. -I, Kusuhara M. , Ulevitch RJ , Berk BC , Lee J. -D. Big MAP kinase 1 (BMK1) is a redox sensitive kinase. J Biol Chem 1996;271:16586-90.

22.

Duff JL , Berk BC , Corson MA Angiotensin II stimulates the pp44 and pp42 MAPKs in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun 1992 ;188:257-64.

23.

Ushi-Fukai M. , Alexander RW , Akers M. , Griendling KK P38 mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. J Biol Chem 1998 ;273:15022-9.

24.

Schmitz U. , Ishida T. , Ishida M. et al. Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: role of activation of JNK. Circ Res 1998;82:1272-8.

25.

Wen Y. , Scott S. , Liu Y. , Gonzales N. , Nadler JL Evidence that angiotensin II and lipoxygenase products activate c-Jun NH2-terminal kinase. Circ Res 1997;81:651-5.

26.

Wei C. , Papadimitriou J. Evaluation of cardiomyocyte viability after cardiac tissue incubated in special culture system. Microscopy and Microanalysis 2000;6:620-1.

27.

Wei C. , Heublein DM , McKinley L. et al. Natriuretic peptide system in human heart failure. Circulation 1993;88:1004-9.

28.

Wei C. , LermanA, Rodeheffer RJ et al. Endothelin in human congestive heart failure. Circulation 1994;89:1580-6.

29.

Wang Y. , Su B. , Sah VP , Brown JH , Han J. , Chien KR Cardiac hypertrophy induced by mitogen-activate protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase family. J Biol Chem 1998;273:5423-6.

30.

Wang,Y., Huang S. , Shah VP et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem 1998;273:2161-8.

31.

Rogg H. , De Gasparo M. , Graedel E. et al. Angiotensin-II receptor subtypes in human atria and evidence for alterations in patients with cardiac dysfunction. Eur Heart J 1996;17:1112-0.

32.

Haywood GA , Gullestad L. , Katsuya T. et al. AT1 and AT2 angiotensin receptor gene expression in human heart failure. Circulation 1997;95:1201-6.

33.

Dzau VJ Cardiac renin-angiotensin system: molecular and functional aspects . AmJMed 1988;84(suppl 3A):22-7.

34.

Dzau VJ , Gibbons GH , Pratt RE Molecular mechanism of vascular renin-angiotensin system in myointimal hyperplasia . Hypertension 1991;18:II-100-II-105.

35.

Natarajan R. , Gonzales N. , Lanting L. , Nadler J. Role of the lipoxygenase pathway in angiotensin II induced vascular smooth muscle cell hypertrophy .Hypertension 1994;23(suppl I):I-142-I-147.

36.

37.

Force T. , Bonventre JV Growth factors and mitogen-activated protein kinases. Hypertension 1998;31(pt 2):152-161.

38.

Gupta S. , Barrett T. , Whitmarsh AJ et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 1996;15:2760-70.

39.

Raingeaud J. , Gupta S. , Rogers JS et al. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995 ;270:7420-6.

40.

Tan Y. , Rouse J. , Zhang A. , Cariati S. , Cohen P. , Comb MJ FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 1996 ;15:4629-42.

41.

Natarajan R. , Scott S. , Bai W. , Yerneni KKV , Nadler J. Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. Hypertension 1999;33[part II]:378-84.

42.

Geisterifer AA , Peach MJ , Owens GK Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 1988;62:749-56.

43.

Sadoshima J. , Izumo S. The heterotrimeric Gq protein-coupled angiotensin II receptor activates p21ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes. EMBO J 1996;15:775-87.

44.

Stoll M. , Steckelings U. , Paul M. , Bottari S. , Metzger R. , Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 1995;95:651-7.

45.

Booz GW , Baker KM Role of type 1 and type 2 angiotensin receptors in angiotensin II-induced cardiomyocyte hypertrophy.Hypertension 1996 ;28:635-40.

46.

Ohkubo N. , Matsubara H. , NozawaY. et al. Angiotensin type 2 receptors are re-expressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation 1997;96:3954-62.

47.

Bedecs K. , Elbaz N. , Sutren M. et al. Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase . Biochem J 1997;325:449-54.