Upregulation of connexin43 by glucose deprivation in H9c2 cells via the extracellular signal‑regulated kinase/mitogen‑activated protein kinase signaling pathway

Wang,Guangyu; Bi,Yaguang; Liu,Xiangdong; Wei,Meng; Zhang,Qingyong

doi:10.3892/mmr.2017.7967

Upregulation of connexin43 by glucose deprivation in H9c2 cells via the extracellular signal‑regulated kinase/mitogen‑activated protein kinase signaling pathway

Authors:
- Guangyu Wang
- Yaguang Bi
- Xiangdong Liu
- Meng Wei
- Qingyong Zhang
View Affiliations

Affiliations: Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
Published online on: November 6, 2017 https://doi.org/10.3892/mmr.2017.7967
Pages: 729-734
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Cardiac connexin43 (Cx43) serves an essential role in maintaining the functional integrity of the heart. The present study investigated the effect of glucose deprivation (GD) on Cx43 protein expression levels in H9c2 cells, and demonstrated that following 2 h GD, Cx43 protein expression levels in H9c2 cells increased by ~68%. In addition, GD activated the extracellular signal‑regulated kinase (ERK)/mitogen‑activated protein kinase (MAPK) signaling pathway, which regulated the expression levels of cardiac Cx43. A MAPK inhibitor and U0126, an ERK inhibitor, abolished the effects of GD on Cx43 expression levels. Under GD, the protein expression levels of Beclin‑1, p62 and LC3 were augmented, and were decreased in the presence of ERK inhibitor or siRNA‑ERK. In addition, H9c2 cells exposed to GD exhibited marked increase in LDH release and decreased MTT reduction activity, all of which were not significantly reversed by U0126 treatment. Therefore, the ERK/MAPK signaling pathway may be involved in elevating cardiac Cx43 expression levels under GD in H9c2 cells.

View Figures

View References

1	Yeh HI, Lee PY, Su CH, Tian TY, Ko YS and Tsai CH: Reduced expression of endothelial connexins 43 and 37 in hypertensive rats is rectified after 7-day carvedilol treatment. Am J Hypertens. 19:129–135. 2006. View Article : Google Scholar : PubMed/NCBI
2	Rutledge CA, Ng FS, Sulkin MS, Greener ID, Sergeyenko AM, Liu H, Gemel J, Beyer EC, Sovari AA, Efimov IR and Dudley SC: c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. J Am Coll Cardiol. 63:928–934. 2014. View Article : Google Scholar : PubMed/NCBI
3	Greener ID, Sasano T, Wan X, Igarashi T, Strom M, Rosenbaum DS and Donahue JK: Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction. J Am Coll Cardiol. 60:1103–1110. 2012. View Article : Google Scholar : PubMed/NCBI
4	Brisset AC, Isakson BE and Kwak BR: Connexins in vascular physiology and pathology. Antioxid Redox Signal. 11:267–282. 2009. View Article : Google Scholar : PubMed/NCBI
5	Vozzi C, Dupont E, Coppen SR, Yeh HI and Severs NJ: Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol. 31:991–1003. 1999. View Article : Google Scholar : PubMed/NCBI
6	Giepmans BN: Gap junctions and connexin-interacting proteins. Cardiovasc Res. 62:233–245. 2004. View Article : Google Scholar : PubMed/NCBI
7	Fernandes R, Girão H and Pereira P: High glucose down-regulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism. J Biol Chem. 279:27219–27224. 2004. View Article : Google Scholar : PubMed/NCBI
8	Lin H, Ogawa K, Imanaga I and Tribulova N: Remodeling of connexin 43 in the diabetic rat heart. Mol Cell Biochem. 290:69–78. 2006. View Article : Google Scholar : PubMed/NCBI
9	Hesketh GG, Shah MH, Halperin VL, Cooke CA, Akar FG, Yen TE, Kass DA, Machamer CE, Van Eyk JE and Tomaselli GF: Ultrastructure and regulation of lateralized connexin43 in the failing heart. Circ Res. 106:1153–1163. 2010. View Article : Google Scholar : PubMed/NCBI
10	Kanno S, Kovacs A, Yamada KA and Saffitz JE: Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice. J Am Coll Cardiol. 41:681–686. 2003. View Article : Google Scholar : PubMed/NCBI
11	Wang HH, Kung CI, Tseng YY, Lin YC, Chen CH, Tsai CH and Yeh HI: Activation of endothelial cells to pathological status by down-regulation of connexin43. Cardiovasc Res. 79:509–518. 2008. View Article : Google Scholar : PubMed/NCBI
12	Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, Woodward M, Ninomiya T, Neal B, MacMahon S, et al: Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 363:1410–1418. 2010. View Article : Google Scholar : PubMed/NCBI
13	Hilsted J, Bonde-Petersen F, Nørgaard MB, Greniman M, Christensen NJ, Parving HH and Suzuki M: Haemodynamic changes in insulin-induced hypoglycaemia in normal man. Diabetologia. 26:328–332. 1984. View Article : Google Scholar : PubMed/NCBI
14	Dave KR, Tamariz J, Desai KM, Brand FJ, Liu A, Saul I, Bhattacharya SK and Pileggi A: Recurrent hypoglycemia exacerbates cerebral ischemic damage in streptozotocin-induced diabetic rats. Stroke. 42:1404–1411. 2011. View Article : Google Scholar : PubMed/NCBI
15	Robinson RT, Harris ND, Ireland RH, Lee S, Newman C and Heller SR: Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes. 52:1469–1474. 2003. View Article : Google Scholar : PubMed/NCBI
16	Dandona P, Chaudhuri A and Dhindsa S: Proinflammatory and prothrombotic effects of hypoglycemia. Diabetes Care. 33:1686–1687. 2010. View Article : Google Scholar : PubMed/NCBI
17	Wang CY, Liu HJ, Chen HJ, Lin YC, Wang HH, Hung TC and Yeh HI: AGE-BSA down-regulates endothelial connexin43 gap junctions. BMC Cell Biol. 12:192011. View Article : Google Scholar : PubMed/NCBI
18	Lee KM, Kwon JY, Lee KW and Lee HJ: Ascorbic acid 6-palmitate suppresses gap-junctional intercellular communication through phosphorylation of connexin 43 via activation of the MEK-ERK pathway. Mutat Res. 660:51–56. 2009. View Article : Google Scholar : PubMed/NCBI
19	Zhao Y, Yu L, Xu S, Qiu F, Fan Y and Fu G: Down-regulation of connexin43 gap junction by serum deprivation in human endothelial cells was improved by (−)-Epigallocatechin gallate via ERK MAP kinase pathway. Biochem Biophys Res Commun. 404:217–222. 2011. View Article : Google Scholar : PubMed/NCBI
20	Yu L, Zhao Y, Xu S, Ding F, Jin C, Fu G and Weng S: Advanced glycation end product (AGE)-AGE receptor (RAGE) system upregulated connexin43 expression in rat cardiomyocytes via PKC and Erk MAPK pathways. Int J Mol Sci. 14:2242–2257. 2013. View Article : Google Scholar : PubMed/NCBI
21	Jia G, Cheng G, Gangahar DM and Agrawal DK: Involvement of connexin 43 in angiotensin II-induced migration and proliferation of saphenous vein smooth muscle cells via the MAPK-AP-1 signaling pathway. J Mol Cell Cardiol. 44:882–890. 2008. View Article : Google Scholar : PubMed/NCBI
22	Bejarano E, Girao H, Yuste A, Patel B, Marques C, Spray DC, Pereira P and Cuervo AM: Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner. Mol Biol Cell. 23:2156–2169. 2012. View Article : Google Scholar : PubMed/NCBI
23	Mitchener JS, Shelburne JD, Bradford WD and Hawkins HK: Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. Am J Pathol. 83:485–492. 1976.PubMed/NCBI
24	Lichtenstein A, Minogue PJ, Beyer EC and Berthoud VM: Autophagy: A pathway that contributes to connexin degradation. J Cell Sci. 124:910–920. 2011. View Article : Google Scholar : PubMed/NCBI
25	Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H and Johansen T: p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 171:603–614. 2005. View Article : Google Scholar : PubMed/NCBI
26	McLachlan CS, Almsherqi ZA, Mossop P, Suzuki J, Leong ST and Deng Y: Down regulation of immuno-detectable cardiac connexin-43 in BALB/c mice following acute fasting. Int J Cardiol. 136:99–102. 2009. View Article : Google Scholar : PubMed/NCBI
27	Garcia-Dorado D, Inserte J, Ruiz-Meana M, González MA, Solares J, Juliá M, Barrabés JA and Soler-Soler J: Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion. Circulation. 96:3579–3586. 1997. View Article : Google Scholar : PubMed/NCBI