β-adrenergic stimulation activates protein kinase Cε and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy

Li,Lin; Cai,Hongyan; Liu,Hua; Guo,Tao

doi:10.3892/mmr.2015.3316

β-adrenergic stimulation activates protein kinase Cε and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy

Authors:
- Lin Li
- Hongyan Cai
- Hua Liu
- Tao Guo
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Affiliations: Department of Cardiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Clinical Laboratory, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
Published online on: February 6, 2015 https://doi.org/10.3892/mmr.2015.3316
Pages: 4373-4380

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Abstract

The cardiac adrenergic signaling pathway is important in the induction of cardiac hypertrophy. The cardiac adrenergic pathway involves two main branches, phospholipase C (PLC)/protein kinase C (PKC) and the adenylate cyclase (cAMPase)/protein kinase A (PKA) signaling pathways. It is hypothesized that PLC/PKC and cAMPase/PKA are activated by the α‑adrenergic receptor (αAR) and the β‑adrenergic receptor (βAR), respectively. Previous studies have demonstrated that exchange protein directly activated by cAMP (Epac), a guanine exchange factor, activates phospholipase Cε. It is possible that there are βAR‑activated PKC pathways mediated by Epac and PLC. In the present study, the role of Epac and PLC in βAR activated PKC pathways in cardiomyocytes was investigated. It was found that PKCε activation and translocation were induced by the βAR agonist, isoproterenol (Iso). Epac agonist 8‑CPT‑2'OMe‑cAMP also enhanced PKCε activation. βAR stimulation activated PKCε in the cardiomyocytes and was regulated by Epac. Iso‑induced change in PKCε was not affected in the cardiomyocytes, which were infected with adenovirus coding rabbit muscle cAMP‑dependent protein kinase inhibitor. However, Iso‑induced PKCε activation was inhibited by the PLC inhibitor, U73122. The results suggested that Iso‑induced PKCε activation was independent of PKA, but was regulated by PLC. To further investigate the downstream signal target of PKCε activation, the expression of phosphorylated extracellular signal‑regulated kinase (pERK)1/2 and the levels of ERK phosphorylation was analyzed. The results revealed that Iso‑induced PKCε activation led to an increase in the expression of pERK1/2. ERK phosphorylation was inhibited by the PKCε inhibitor peptide. Taken together, these data demonstrated that the βAR is able to activate PKCε dependent on Epac and PLC, but independent of PKA.

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1	Lorell BH and Carabello BA: Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 102:470–479. 2000. View Article : Google Scholar : PubMed/NCBI
2	Diwan A and Dorn GW II: Decompensation of cardiac hypertrophy: cellular mechanisms and novel therapeutic targets. Physiology (Bethesda). 22:56–64. 2007. View Article : Google Scholar
3	Artham SM, Lavie CJ, Milani RV, Patel DA, Verma A and Ventura HO: Clinical impact of left ventricular hypertrophy and implications for regression. Prog Cardiovasc Dis. 52:153–167. 2009. View Article : Google Scholar : PubMed/NCBI
4	Vakili BA, Okin PM and Devereux RB: Prognostic implications of left ventricular hypertrophy. Am Heart J. 141:334–341. 2001. View Article : Google Scholar : PubMed/NCBI
5	Frey N, Katus HA, Olson EN and Hill JA: Hypertrophy of the heart a new therapeutic target? Circulation. 109:1580–1589. 2004. View Article : Google Scholar : PubMed/NCBI
6	Dorn GW IInd: Adrenergic pathways and left ventricular remodeling. J Card Fail 8 Suppl. 6:370–373. 2002. View Article : Google Scholar
7	Barki-Harrington L, Perrino C and Rockman HA: Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc Res. 63:391–402. 2004. View Article : Google Scholar : PubMed/NCBI
8	Wang W, Zhu W, Wang S, Yang D, Crow MT, Xiao RP and Cheng H: Sustained β1-adrenergic stimulation modulates cardiac contractility by ca²⁺/calmodulin kinase signaling pathway. Circ Res. 95:798–806. 2004. View Article : Google Scholar : PubMed/NCBI
9	Movsesian MA and Bristow MR: Alterations in cAMP-mediated signaling and their role in the pathophysiology of dilated cardiomyopathy. Curr Top Dev Biol. 68:25–48. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lohse MJ, Engelhardt S and Eschenhagen T: What is the role of β-adrenergic signaling in heart failure? Circ Res. 93:896–906. 2003. View Article : Google Scholar : PubMed/NCBI
11	Osadchii OE: Cardiac hypertrophy induced by sustained beta-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev. 12:66–86. 2007. View Article : Google Scholar : PubMed/NCBI
12	Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE and Graybiel AM: A family of camp-binding proteins that directly activate rap1. Science. 282:2275–2279. 1998. View Article : Google Scholar : PubMed/NCBI
13	de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A and Bos JL: Epac is a rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature. 396:474–477. 1998. View Article : Google Scholar : PubMed/NCBI
14	Schmidt M, Evellin S, Weernink PA, Von Dorp F, Rehmann H, Lomasney JW and Jakobs KH: A new phospholipase C-calcium signalling pathway mediated by cyclic AMP and a rap GTPase. Nat Cell Biol. 3:1020–1024. 2001. View Article : Google Scholar : PubMed/NCBI
15	Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW and Jakobs KH: A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat Cell Biol. 3:1020–1024. 2001. View Article : Google Scholar : PubMed/NCBI
16	Hucho TB, Dina OA and Levine JD: Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. J Neurosci. 25:6119–6126. 2005. View Article : Google Scholar : PubMed/NCBI
17	Oestreich EA, Wang H, Malik S, Kaproth-Joslin KA, Blaxall BC, Kelley GG, Dirksen RT and Smrcka AV: Epac-mediated activation of phospholipase Cε plays a critical role in β-adrenergic receptor-dependent enhancement of Ca²⁺ mobilization in cardiac myocytes. J Biol Chem. 282:5488–5495. 2007. View Article : Google Scholar
18	Oestreich EA, Wang H, Malik S, Goonasekera SA, Blaxall BC, Kelley GG, Dirksen RT and Smrcka AV: Epac and phospholipase Cε regulate Ca²⁺ release in the heart by activation of protein kinase Cε and calcium-calmodulin kinase II. J Biol Chem. 284:1514–1522. 2009. View Article : Google Scholar :
19	Churchill E, Budas G, Vallentin A, Koyanagi T and Mochly-Rosen D: PKC isozymes in chronic cardiac disease: possible therapeutic targets? Annu Rev Pharmacol Toxicol. 48:569–599. 2008. View Article : Google Scholar
20	Inagaki K, Churchill E and Mochly-Rosen D: Epsilon protein kinase C as a potential therapeutic target for the ischemic heart. Cardiovasc Res. 70:222–230. 2006. View Article : Google Scholar : PubMed/NCBI
21	Mackay K and Mochly-Rosen D: Localization, anchoring, and functions of protein kinase C isozymes in the heart. J Mol Cell Cardiol. 33:1301–1307. 2001. View Article : Google Scholar : PubMed/NCBI
22	Schonwasser DC, Marais RM, Marshall CJ and Parker PJ: Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel and atypical protein kinase C isotypes. Mol Cell Biol. 18:790–798. 1998.
23	Nilsson D, Gustafsson L, Wackenfors A, Gesslein B, Edvinsson L, Paulsson P, Ingemansson R and Malmsjo M: Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways. BMC Cardiovasc Disord. 8:212008. View Article : Google Scholar : PubMed/NCBI
24	Wang Y: Mitogen-activated protein kinases in heart development and diseases. Circulation. 116:1413–1423. 2007. View Article : Google Scholar : PubMed/NCBI
25	Iwaki K, Sukhatme VP, Shubeita HE and Chien KR: Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; egr-1 induction is primarily an alpha 1-mediated response. J Biol Chem. 265:13809–13817. 1990.PubMed/NCBI
26	Mochly-Rosen D: Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science. 268:247–251. 1995. View Article : Google Scholar : PubMed/NCBI
27	Mochly-Rosen D and Gordon AS: Anchoring proteins for protein kinase C: a means for isozyme selectivity. FASEB J. 12:35–42. 1998.PubMed/NCBI
28	Vincent F, Duquesnes N, Christov C, Damy T, Samuel JL and Crozatier B: Dual level of interactions between calcineurin and PKC-epsilon in cardiomyocyte stretch. Cardiovasc Res. 71:97–107. 2006. View Article : Google Scholar : PubMed/NCBI
29	Bos JL: Epac: a new cAMP target and new avenues in cAMP research. Nat Rev Mol Cell Biol. 4:733–738. 2003. View Article : Google Scholar : PubMed/NCBI
30	Newton AC: Protein kinase C: structural and spatial regulation by phosphorylation, cofactors and macromolecular interactions. Chem Rev. 101:2353–2364. 2001. View Article : Google Scholar : PubMed/NCBI
31	Gudermann T, Schoneberg T and Schultz G: Functional and structural complexity of signal transduction via G-protein-coupled receptors. Annu Rev Neurosci. 20:399–427. 1997. View Article : Google Scholar : PubMed/NCBI
32	Parada CA, Reichling DB and Levine JD: Chronic hyperalgesic priming in the rat involves a novel interaction between cAMP and PKCε second messenger pathways. Pain. 113:185–190. 2005. View Article : Google Scholar
33	Gold MS, Levine JD and Correa AM: Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J Neurosci. 18:10345–10355. 1998.PubMed/NCBI
34	Fan L, Ma J, Chen YH and Chen XQ: Antioxidant and antimicrobial phenolic compounds from Setaria viridis. Chem Nat Comp. 50:433–437. 2014. View Article : Google Scholar
35	Lu ZX, Quazi NH, Deady LW and Polya GM: Selective inhibition of cyclic AMP-dependent protein kinase by isoquinoline derivatives. Biol Chem Hoppe Seyler. 377:373–384. 1996. View Article : Google Scholar : PubMed/NCBI
36	Bos JL: Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 31:680–686. 2006. View Article : Google Scholar : PubMed/NCBI
37	Holz GG, Kang G, Harbeck M, Roe MW and Chepurny OG: Cell physiology of cAMP sensor epac. J Physiol. 577:5–15. 2006. View Article : Google Scholar : PubMed/NCBI
38	Morel E, Marcantoni A, Gastineau M, Birkedal R, Rochais F, Garnier A, Lompree A, Vandecasteele G and Lezoualch F: CAMP-binding protein epac induces cardiomyocyte hypertrophy. Circ Res. 97:1296–1304. 2005. View Article : Google Scholar : PubMed/NCBI
39	Métrich M, Morel E, Berthouze M, Pereira L, Charron P, Gomez A and Lezoualch F: Functional characterization of the cAMP-binding proteins Epac in cardiac myocytes. Pharmacol Rep. 61:146–153. 2009. View Article : Google Scholar : PubMed/NCBI
40	Wang H, Oestreich EA, Maekawa N, Bullard TA, Vikstrom KL, Dirksen RT, Kelley GG, Blaxall BC and Smrcka AV: Phospholipase C epsilon modulates beta-adrenergic Receptor-dependent cardiac contraction and inhibits cardiac hypertrophy. Circ Res. 97:1305–1313. 2005. View Article : Google Scholar : PubMed/NCBI
41	Kehat I and Molkentin JD: Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann N Y Acad Sci. 1188:96–102. 2010. View Article : Google Scholar : PubMed/NCBI
42	Bueno OF and Molkentin JD: Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res. 91:776–781. 2002. View Article : Google Scholar : PubMed/NCBI
43	House SL, House BE, Glascock B, Kimball T, Nusayr E, Schultz JE and Doetschaman T: Fibroblast growth factor 2 mediates isoproterenol-induced cardiac hypertrophy through activation of the extracellular regulated kinase. Mol Cell Pharmacol. 2:143–154. 2010.
44	Zhang GX, Kimura S, Murao K, Yu X, Obata K, Matsuyoshi H and Takaki M: Effects of angiotensin type I receptor blockade on the cardiac RAF/MEK/ERK cascade activated via adrenergic receptors. J Pharmacol Sci. 113:224–233. 2010. View Article : Google Scholar : PubMed/NCBI
45	Takeishi Y, Ping P, Bolli R, Kirkpatrick DL, Hoit B and Walsh RA: Transgenic overexpression of constitutively active protein kinase cε causes concentric cardiac hypertrophy. Circ Res. 86:1218–1223. 2000. View Article : Google Scholar : PubMed/NCBI
46	Morisco C, Marrone C, Galeotti J, Shao D, Vatner DE, Vatner SF and Sadoshima J: Endocytosis machinery is required for β1-adrenergic receptor-induced hypertrophy in neonatal rat cardiac myocytes. Cardiovasc Res. 78:36–44. 2008. View Article : Google Scholar : PubMed/NCBI