LKB1/AMPK pathway mediates resistin‑induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

Liu,Peng; Cheng,Guan‑Chang; Ye,Qun‑Hui; Deng,Yong‑Zhi; Wu,Lin

doi:10.3892/br.2016.593

LKB1/AMPK pathway mediates resistin‑induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

Authors:
- Peng Liu
- Guan‑Chang Cheng
- Qun‑Hui Ye
- Yong‑Zhi Deng
- Lin Wu
View Affiliations

Affiliations: Department of Cardiovascular Surgery, The Affiliated Cardiovascular Hospital of Shanxi Medical University, and Shanxi Cardiovascular Hospital (Institute), Taiyuan, Shanxi 030024, P.R. China, Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng, Henan 475000, P.R. China
Published online on: February 5, 2016 https://doi.org/10.3892/br.2016.593
Pages: 387-391

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Resistin has been previously demonstrated to induce cardiac hypertrophy, however, the underlying molecular mechanisms of resistin‑induced cardiac hypertrophy remain unclear. Using H9c2 cells, the present study investigated the liver kinase B1 (LKB1)/adenosine monophosphate‑activated protein kinase (AMPK) signaling pathway for a potential role in mediating resistin‑induced cardiomyocyte hypertrophy. Treatment of H9c2 cells with resistin increased cell surface area, protein synthesis, and expression of hypertrophic marker brain natriuretic peptide and β‑myosin heavy chain. Treatment with metformine attenuated these effects of resistin. Furthermore, treatment with resistin decreased phosphorylation of LKB1 and AMPK, whereas pretreatment with metformin increased phosphorylation of LKB1 and AMPK that is reduced by resistin. These results suggest that resistin induces cardiac hypertrophy through the inactivation of the LKB1/AMPK cell signaling pathway.

View Figures

View References

1	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
2	Carreño JE, Apablaza F, Ocaranza MP and Jalil JE: Cardiac hypertrophy: Molecular and cellular events. Rev Esp Cardiol. 59:473–486. 2006.(In Spanish). View Article : Google Scholar : PubMed/NCBI
3	Alessi DR, Sakamoto K and Bayascas JR: LKB1-dependent signaling pathways. Annu Rev Biochem. 75:137–163. 2006. View Article : Google Scholar : PubMed/NCBI
4	Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA and Cantley LC: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 101:3329–3335. 2004. View Article : Google Scholar : PubMed/NCBI
5	Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, Alessi DR and Hardie DG: Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2:282003. View Article : Google Scholar : PubMed/NCBI
6	Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR and Clevers HC: Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 22:3062–3072. 2003. View Article : Google Scholar : PubMed/NCBI
7	Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA and Kemp BE: Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 271:611–614. 1996. View Article : Google Scholar : PubMed/NCBI
8	Alexander A and Walker CL: The role of LKB1 and AMPK in cellular responses to stress and damage. FEBS Lett. 585:952–957. 2011. View Article : Google Scholar : PubMed/NCBI
9	Zaha VG and Young LH: AMP-activated protein kinase regulation and biological actions in the heart. Circ Res. 111:800–814. 2012. View Article : Google Scholar : PubMed/NCBI
10	Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS and Lazar MA: The hormone resistin links obesity to diabetes. Nature. 409:307–312. 2001. View Article : Google Scholar : PubMed/NCBI
11	Kim M, Oh JK, Sakata S, Liang I, Park W, Hajjar RJ and Lebeche D: Role of resistin in cardiac contractility and hypertrophy. J Mol Cell Cardiol. 45:270–280. 2008. View Article : Google Scholar : PubMed/NCBI
12	Graveleau C, Zaha VG, Mohajer A, Banerjee RR, Dudley-Rucker N, Steppan CM, Rajala MW, Scherer PE, Ahima RS, Lazar MA and Abel ED: Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes and oligomerization is required for this biological action. J Biol Chem. 280:31679–31685. 2005. View Article : Google Scholar : PubMed/NCBI
13	Kang S, Chemaly ER, Hajjar RJ and Lebeche D: Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem. 286:18465–18473. 2011. View Article : Google Scholar : PubMed/NCBI
14	Sun B, Huo R, Sheng Y, Li Y, Xie X, Chen C, Liu HB, Li N, Li CB, Guo WT, et al: Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis and fibrosis in experimentally pathological cardiac hypertrophy. Hypertension. 61:352–360. 2013. View Article : Google Scholar : PubMed/NCBI
15	Merten KE, Jiang Y and Kang YJ: Zinc inhibits doxorubicin-activated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells. Exp Biol Med (Maywood). 232:682–689. 2007.PubMed/NCBI
16	Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M and Cantley LC: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 310:1642–1646. 2005. View Article : Google Scholar : PubMed/NCBI
17	Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 108:1167–1174. 2001. View Article : Google Scholar : PubMed/NCBI
18	Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH and Smith SA: Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun. 300:472–476. 2003. View Article : Google Scholar : PubMed/NCBI
19	Lu SC, Shieh WY, Chen CY, Hsu SC and Chen HL: Lipopolysaccharide increases resistin gene expression in vivo and in vitro. FEBS Lett. 530:158–162. 2002. View Article : Google Scholar : PubMed/NCBI
20	Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H and Patsch JR: Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun. 309:286–290. 2003. View Article : Google Scholar : PubMed/NCBI
21	Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ and Lazar MA: An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med. 1:e452004. View Article : Google Scholar : PubMed/NCBI
22	Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE, et al: Regulation of fasted blood glucose by resistin. Science. 303:1195–1198. 2004. View Article : Google Scholar : PubMed/NCBI
23	Muse ED, Obici S, Bhanot S, Monia BP, McKay RA, Rajala MW, Scherer PE and Rossetti L: Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest. 114:232–239. 2004. View Article : Google Scholar : PubMed/NCBI
24	Rajala MW, Obici S, Scherer PE and Rossetti L: Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest. 111:225–230. 2003. View Article : Google Scholar : PubMed/NCBI
25	Chemaly ER, Hadri L, Zhang S, Kim M, Kohlbrenner E, Sheng J, Liang L, Chen J, K-Raman P, Hajjar RJ and Lebeche D: Long-term in vivo resistin overexpression induces myocardial dysfunction and remodeling in rats. J Mol Cell Cardiol. 51:144–155. 2011. View Article : Google Scholar : PubMed/NCBI
26	Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, Westra WH, Herman JG and Sidransky D: Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62:3659–3662. 2002.PubMed/NCBI
27	Guldberg P, Straten Thor P, Ahrenkiel V, Seremet T, Kirkin AF and Zeuthen J: Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Oncogene. 18:1777–1780. 1999. View Article : Google Scholar : PubMed/NCBI
28	McCabe MT, Powell DR, Zhou W and Vertino PM: Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells. Cancer Genet Cytogenet. 197:130–141. 2010. View Article : Google Scholar : PubMed/NCBI
29	Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L and Cantley LC: Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 33:237–247. 2009. View Article : Google Scholar : PubMed/NCBI
30	Oakhill JS, Chen ZP, Scott JW, Steel R, Castelli LA, Ling N, Macaulay SL and Kemp BE: β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci USA. 107:19237–19241. 2010. View Article : Google Scholar : PubMed/NCBI
31	Dolinsky VW, Chan AY, Frayne Robillard I, Light PE, Des Rosiers C and Dyck JR: Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation. 119:1643–1652. 2009. View Article : Google Scholar : PubMed/NCBI
32	Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA and Colucci WS: Post-translational modification of serine/threonine kinase LKB1 via adduction of the reactive lipid species 4-Hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly inhibits kinase activity. J Biol Chem. 287:42400–42406. 2012. View Article : Google Scholar : PubMed/NCBI
33	El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M and Leverve X: Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 275:223–228. 2000. View Article : Google Scholar : PubMed/NCBI
34	Owen MR, Doran E and Halestrap AP: Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 348:607–614. 2000. View Article : Google Scholar : PubMed/NCBI
35	Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS and Shaw RJ: LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 23:143–158. 2013. View Article : Google Scholar : PubMed/NCBI
36	Zhou W, Marcus AI and Vertino PM: Dysregulation of mTOR activity through LKB1 inactivation. Chin J Cancer. 32:427–433. 2013. View Article : Google Scholar : PubMed/NCBI
37	Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA and Colucci WS: The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1-p70S6K-RPS6 signaling. Free Radic Biol Med. 82:137–146. 2015. View Article : Google Scholar : PubMed/NCBI
38	Kuwabara Y, Horie T, Baba O, Watanabe S, Nishiga M, Usami S, Izuhara M, Nakao T, Nishino T, Otsu K, et al: MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. Circ Res. 116:279–288. 2015. View Article : Google Scholar : PubMed/NCBI
39	Dolinsky VW, Chakrabarti S, Pereira TJ, Oka T, Levasseur J, Beker D, Zordoky BN, Morton JS, Nagendran J, Lopaschuk GD, et al: Resveratrol prevents hypertension and cardiac hypertrophy in hypertensive rats and mice. Biochim Biophys Acta. 1832:1723–1733. 2013. View Article : Google Scholar : PubMed/NCBI
40	Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, Samant S, Ravindra PV, Isbatan A and Gupta MP: Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem. 285:3133–3144. 2010. View Article : Google Scholar : PubMed/NCBI