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01.12.2020 | Original Contribution

Hyperglycemia regulates cardiac K⁺ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways

verfasst von: Bence Hegyi, Johanna M. Borst, Logan R. J. Bailey, Erin Y. Shen, Austen J. Lucena, Manuel F. Navedo, Julie Bossuyt, Donald M. Bers

Erschienen in: Basic Research in Cardiology | Ausgabe 6/2020

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Abstract

Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K⁺ channel remodeling and increased arrhythmia risk. However, the exact signaling mechanism by which diabetic hyperglycemia regulates cardiac K⁺ channels remains elusive. Here, we show that acute hyperglycemia increases inward rectifier K⁺ current (I_K1), but reduces the amplitude and inactivation recovery time of the transient outward K⁺ current (I_to) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, I_K1 amplitude and I_to recovery effects (but not I_to amplitude) were prevented by the Ca²⁺/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, and O-GlcNAc-resistant CaMKIIδ-S280A knock-in. I_to reduction was prevented by inhibition of protein kinase C (PKC) and NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models of chronic diabetes (streptozotocin, db/db, and high-fat diet), heart failure, and CaMKIIδ overexpression, both I_to and I_K1 were reduced in line with the downregulated K⁺ channel expression. However, I_K1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances I_K1 and I_to recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces I_to amplitude via a NOX2-ROS-PKC pathway. Moreover, chronic hyperglycemia during diabetes and CaMKII activation downregulate K⁺ channel expression and function, which may further increase arrhythmia susceptibility.

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Aflaki M, Qi XY, Xiao L, Ordog B, Tadevosyan A, Luo X, Maguy A, Shi Y, Tardif JC, Nattel S (2014) Exchange protein directly activated by cAMP mediates slow delayed-rectifier current remodeling by sustained beta-adrenergic activation in guinea pig hearts. Circ Res 114:993–1003. https://doi.org/10.1161/CIRCRESAHA.113.302982CrossRefPubMed

Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213–3223. https://doi.org/10.1161/CIRCULATIONAHA.106.679597CrossRefPubMed

Brouillette J, Clark RB, Giles WR, Fiset C (2004) Functional properties of K⁺ currents in adult mouse ventricular myocytes. J Physiol 559:777–798. https://doi.org/10.1113/jphysiol.2004.063446CrossRefPubMedPubMedCentral

Brown DW, Giles WH, Greenlund KJ, Valdez R, Croft JB (2001) Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the Third National Health and Nutrition Examination Survey. J Cardiovasc Risk 8:227–233. https://doi.org/10.1177/174182670100800407CrossRefPubMed

Burgoyne JR, Mongue-Din H, Eaton P, Shah AM (2012) Redox signaling in cardiac physiology and pathology. Circ Res 111:1091–1106. https://doi.org/10.1161/CIRCRESAHA.111.255216CrossRefPubMed

Ceriello A (2005) Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes 54:1–7. https://doi.org/10.2337/diabetes.54.1.1CrossRefPubMed

Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, Sheridan PJ, Heller SR (2014) Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 63:1738–1747. https://doi.org/10.2337/db13-0468CrossRefPubMed

Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR (2012) Cell signaling through protein kinase C oxidation and activation. Int J Mol Sci 13:10697–10721. https://doi.org/10.3390/ijms130910697CrossRefPubMedPubMedCentral

Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Juni P, Lettino M, Marx N, Mellbin LG, Ostgren CJ, Rocca B, Roffi M, Sattar N, Seferovic PM, Sousa-Uva M, Valensi P, Wheeler DC, Group ESCSD (2020) 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 41:255–323. https://doi.org/10.1093/eurheartj/ehz486CrossRefPubMed

10.

Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O’Donnell SE, Aykin-Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME (2008) A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133:462–474. https://doi.org/10.1016/j.cell.2008.02.048CrossRefPubMedPubMedCentral

11.

Erickson JR, Pereira L, Wang L, Han G, Ferguson A, Dao K, Copeland RJ, Despa F, Hart GW, Ripplinger CM, Bers DM (2013) Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502:372–376. https://doi.org/10.1038/nature12537CrossRefPubMedPubMedCentral

12.

Geraldes P, King GL (2010) Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106:1319–1331. https://doi.org/10.1161/CIRCRESAHA.110.217117CrossRefPubMedPubMedCentral

13.

Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070. https://doi.org/10.1161/CIRCRESAHA.110.223545CrossRefPubMedPubMedCentral

14.

Hegyi B, Banyasz T, Izu LT, Belardinelli L, Bers DM, Chen-Izu Y (2018) beta-adrenergic regulation of late Na⁺ current during cardiac action potential is mediated by both PKA and CaMKII. J Mol Cell Cardiol 123:168–179. https://doi.org/10.1016/j.yjmcc.2018.09.006CrossRefPubMed

15.

Hegyi B, Bers DM, Bossuyt J (2019) CaMKII signaling in heart diseases: emerging role in diabetic cardiomyopathy. J Mol Cell Cardiol 127:246–259. https://doi.org/10.1016/j.yjmcc.2019.01.001CrossRefPubMed

16.

Hegyi B, Bossuyt J, Ginsburg KS, Mendoza LM, Talken L, Ferrier WT, Pogwizd SM, Izu LT, Chen-Izu Y, Bers DM (2018) Altered repolarization reserve in failing rabbit ventricular myocytes: calcium and beta-adrenergic effects on delayed- and inward-rectifier potassium currents. Circ Arrhythm Electrophysiol 11:e005852. https://doi.org/10.1161/CIRCEP.117.005852CrossRefPubMedPubMedCentral

17.

Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49:1939–1945. https://doi.org/10.2337/diabetes.49.11.1939CrossRefPubMed

18.

Jouven X, Lemaitre RN, Rea TD, Sotoodehnia N, Empana JP, Siscovick DS (2005) Diabetes, glucose level, and risk of sudden cardiac death. Eur Heart J 26:2142–2147. https://doi.org/10.1093/eurheartj/ehi376CrossRefPubMed

19.

Jovanovic S, Jovanovic A (2005) High glucose regulates the activity of cardiac sarcolemmal ATP-sensitive K+ channels via 1,3-bisphosphoglycerate: a novel link between cardiac membrane excitability and glucose metabolism. Diabetes 54:383–393. https://doi.org/10.2337/diabetes.54.2.383CrossRefPubMedPubMedCentral

20.

King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166:877–894. https://doi.org/10.1111/j.1476-5381.2012.01911.xCrossRefPubMedPubMedCentral

21.

Kronlage M, Dewenter M, Grosso J, Fleming T, Oehl U, Lehmann LH, Falcao-Pires I, Leite-Moreira AF, Volk N, Grone HJ, Muller OJ, Sickmann A, Katus HA, Backs J (2019) O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure. Circulation 140:580–594. https://doi.org/10.1161/CIRCULATIONAHA.117.031942CrossRefPubMed

22.

Lengyel C, Virag L, Biro T, Jost N, Magyar J, Biliczki P, Kocsis E, Skoumal R, Nanasi PP, Toth M, Kecskemeti V, Papp JG, Varro A (2007) Diabetes mellitus attenuates the repolarization reserve in mammalian heart. Cardiovasc Res 73:512–520. https://doi.org/10.1016/j.cardiores.2006.11.010CrossRefPubMed

23.

Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y, Dalton ND, Peterson KL, Chen J, Bers D, Brown JH (2009) Requirement for Ca²⁺/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest 119:1230–1240. https://doi.org/10.1172/JCI38022CrossRefPubMedPubMedCentral

24.

Lu S, Liao Z, Lu X, Katschinski DM, Mercola M, Chen J, Heller Brown J, Molkentin JD, Bossuyt J, Bers DM (2020) Hyperglycemia acutely increases cytosolic reactive oxygen species via O-linked glcnacylation and camkii activation in mouse ventricular myocytes. Circ Res 126:e80–e96. https://doi.org/10.1161/CIRCRESAHA.119.316288CrossRefPubMed

25.

Luo M, Guan X, Luczak ED, Lang D, Kutschke W, Gao Z, Yang J, Glynn P, Sossalla S, Swaminathan PD, Weiss RM, Yang B, Rokita AG, Maier LS, Efimov IR, Hund TJ, Anderson ME (2013) Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest 123:1262–1274. https://doi.org/10.1172/JCI65268CrossRefPubMedPubMedCentral

26.

Ma J, Hart GW (2013) Protein O-GlcNAcylation in diabetes and diabetic complications. Expert Rev Proteomics 10:365–380. https://doi.org/10.1586/14789450.2013.820536CrossRefPubMedPubMedCentral

27.

Magyar J, Rusznak Z, Szentesi P, Szucs G, Kovacs L (1992) Action potentials and potassium currents in rat ventricular muscle during experimental diabetes. J Mol Cell Cardiol 24:841–853. https://doi.org/10.1016/0022-2828(92)91098-pCrossRefPubMed

28.

Marfella R, Nappo F, De Angelis L, Siniscalchi M, Rossi F, Giugliano D (2000) The effect of acute hyperglycaemia on QTc duration in healthy man. Diabetologia 43:571–575. https://doi.org/10.1007/s001250051345CrossRefPubMed

29.

Meo M, Meste O, Signore S, Sorrentino A, Cannata A, Zhou Y, Matsuda A, Luciani M, Kannappan R, Goichberg P, Leri A, Anversa P, Rota M (2016) Reduction in Kv current enhances the temporal dispersion of the action potential in diabetic myocytes: insights from a novel repolarization algorithm. J Am Heart Assoc. https://doi.org/10.1161/JAHA.115.003078CrossRefPubMedPubMedCentral

30.

Nakamura TY, Coetzee WA, Vega-Saenz De Miera E, Artman M, Rudy B (1997) Modulation of Kv4 channels, key components of rat ventricular transient outward K⁺ current, by PKC. Am J Physiol 273:H1775-1786. https://doi.org/10.1152/ajpheart.1997.273.4.H1775CrossRefPubMed

31.

Nishio S, Teshima Y, Takahashi N, Thuc LC, Saito S, Fukui A, Kume O, Fukunaga N, Hara M, Nakagawa M, Saikawa T (2012) Activation of CaMKII as a key regulator of reactive oxygen species production in diabetic rat heart. J Mol Cell Cardiol 52:1103–1111. https://doi.org/10.1016/j.yjmcc.2012.02.006CrossRefPubMed

32.

Nystoriak MA, Nieves-Cintron M, Nygren PJ, Hinke SA, Nichols CB, Chen CY, Puglisi JL, Izu LT, Bers DM, Dell’acqua ML, Scott JD, Santana LF, Navedo MF (2014) AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca²⁺-activated K⁺ channel remodeling in hyperglycemia and diabetes mellitus. Circ Res 114:607–615. https://doi.org/10.1161/CIRCRESAHA.114.302168CrossRefPubMed

33.

Po SS, Wu RC, Juang GJ, Kong W, Tomaselli GF (2001) Mechanism of alpha-adrenergic regulation of expressed hKv4.3 currents. Am J Physiol Heart Circ Physiol 281:H2518-2527. https://doi.org/10.1152/ajpheart.2001.281.6.H2518CrossRefPubMed

34.

Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM (2001) Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res 88:1159–1167. https://doi.org/10.1161/hh1101.091193CrossRefPubMed

35.

Polina I, Jansen HJ, Li T, Moghtadaei M, Bohne LJ, Liu Y, Krishnaswamy P, Egom EE, Belke DD, Rafferty SA, Ezeani M, Gillis AM, Rose RA (2020) Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes. Proc Natl Acad Sci U S A 117:7990–8000. https://doi.org/10.1073/pnas.1914853117CrossRefPubMedPubMedCentral

36.

Ravens U, Cerbai E (2008) Role of potassium currents in cardiac arrhythmias. Europace 10:1133–1137. https://doi.org/10.1093/europace/eun193CrossRefPubMed

37.

Robles-Flores M, Melendez L, Garcia W, Mendoza-Hernandez G, Lam TT, Castaneda-Patlan C, Gonzalez-Aguilar H (2008) Posttranslational modifications on protein kinase c isozymes. Effects of epinephrine and phorbol esters. Biochim Biophys Acta 1783:695–712. https://doi.org/10.1016/j.bbamcr.2007.07.011CrossRefPubMed

38.

Roeper J, Lorra C, Pongs O (1997) Frequency-dependent inactivation of mammalian A-type K⁺ channel KV1.4 regulated by Ca²⁺/calmodulin-dependent protein kinase. J Neurosci 17:3379–3391CrossRef

39.

Sato T, Kobayashi T, Kuno A, Miki T, Tanno M, Kouzu H, Itoh T, Ishikawa S, Kojima T, Miura T, Tohse N (2014) Type 2 diabetes induces subendocardium-predominant reduction in transient outward K⁺ current with downregulation of Kv4.2 and KChIP2. Am J Physiol Heart Circ Physiol 306:H1054-1065. https://doi.org/10.1152/ajpheart.00414.2013CrossRefPubMed

40.

Schmitt N, Grunnet M, Olesen SP (2014) Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia. Physiol Rev 94:609–653. https://doi.org/10.1152/physrev.00022.2013CrossRefPubMed

41.

Sergeant GP, Ohya S, Reihill JA, Perrino BA, Amberg GC, Imaizumi Y, Horowitz B, Sanders KM, Koh SD (2005) Regulation of Kv4.3 currents by Ca²⁺/calmodulin-dependent protein kinase II. Am J Physiol Cell Physiol 288:C304-313. https://doi.org/10.1152/ajpcell.00293.2004CrossRefPubMed

42.

Slot JW, Geuze HJ, Gigengack S, James DE, Lienhard GE (1991) Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat. Proc Natl Acad Sci U S A 88:7815–7819. https://doi.org/10.1073/pnas.88.17.7815CrossRefPubMedPubMedCentral

43.

Syed AU, Reddy GR, Ghosh D, Prada MP, Nystoriak MA, Morotti S, Grandi E, Sirish P, Chiamvimonvat N, Hell JW, Santana LF, Xiang YK, Nieves-Cintron M, Navedo MF (2019) Adenylyl cyclase 5-generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia. J Clin Invest 129:3140–3152. https://doi.org/10.1172/JCI124705CrossRefPubMedPubMedCentral

44.

Tenma T, Mitsuyama H, Watanabe M, Kakutani N, Otsuka Y, Mizukami K, Kamada R, Takahashi M, Takada S, Sabe H, Tsutsui H, Yokoshiki H (2018) Small-conductance Ca²⁺-activated K⁺ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy. Am J Physiol Heart Circ Physiol 315:H262–H272. https://doi.org/10.1152/ajpheart.00636.2017CrossRefPubMed

45.

Thomas D, Zhang W, Wu K, Wimmer AB, Gut B, Wendt-Nordahl G, Kathofer S, Kreye VA, Katus HA, Schoels W, Kiehn J, Karle CA (2003) Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein. Cardiovasc Res 59:14–26. https://doi.org/10.1016/s0008-6363(03)00386-9CrossRefPubMed

46.

Tran HV, Gore JM, Darling CE, Ash AS, Kiefe CI, Goldberg RJ (2018) Hyperglycemia and risk of ventricular tachycardia among patients hospitalized with acute myocardial infarction. Cardiovasc Diabetol 17:136. https://doi.org/10.1186/s12933-018-0779-8CrossRefPubMedPubMedCentral

47.

Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, McKinsey TA (2004) Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Mol Cell Biol 24:8374–8385. https://doi.org/10.1128/MCB.24.19.8374-8385.2004CrossRefPubMedPubMedCentral

48.

Wagner S, Hacker E, Grandi E, Weber SL, Dybkova N, Sossalla S, Sowa T, Fabritz L, Kirchhof P, Bers DM, Maier LS (2009) Ca/calmodulin kinase II differentially modulates potassium currents. Circ Arrhythm Electrophysiol 2:285–294. https://doi.org/10.1161/CIRCEP.108.842799CrossRefPubMedPubMedCentral

49.

Wu X, Zhang T, Bossuyt J, Li X, McKinsey TA, Dedman JR, Olson EN, Chen J, Brown JH, Bers DM (2006) Local InsP3-dependent perinuclear Ca²⁺ signaling in cardiac myocyte excitation-transcription coupling. J Clin Invest 116:675–682. https://doi.org/10.1172/JCI27374CrossRefPubMedPubMedCentral

50.

Xu H, Guo W, Nerbonne JM (1999) Four kinetically distinct depolarization-activated K⁺ currents in adult mouse ventricular myocytes. J Gen Physiol 113:661–678. https://doi.org/10.1085/jgp.113.5.661CrossRefPubMedPubMedCentral

51.

Xu Z, Patel KP, Lou MF, Rozanski GJ (2002) Up-regulation of K(+) channels in diabetic rat ventricular myocytes by insulin and glutathione. Cardiovasc Res 53:80–88. https://doi.org/10.1016/s0008-6363(01)00446-1CrossRefPubMed

52.

Zhang DM, Chai Y, Erickson JR, Brown JH, Bers DM, Lin YF (2014) Intracellular signalling mechanism responsible for modulation of sarcolemmal ATP-sensitive potassium channels by nitric oxide in ventricular cardiomyocytes. J Physiol 592:971–990. https://doi.org/10.1113/jphysiol.2013.264697CrossRefPubMedPubMedCentral

53.

Zhang T, Maier LS, Dalton ND, Miyamoto S, Ross J Jr, Bers DM, Brown JH (2003) The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res 92:912–919. https://doi.org/10.1161/01.RES.0000069686.31472.C5CrossRefPubMed

54.

Zhang Y, Xiao J, Lin H, Luo X, Wang H, Bai Y, Wang J, Zhang H, Yang B, Wang Z (2007) Ionic mechanisms underlying abnormal QT prolongation and the associated arrhythmias in diabetic rabbits: a role of rapid delayed rectifier K⁺ current. Cell Physiol Biochem 19:225–238. https://doi.org/10.1159/000100642CrossRefPubMed

Titel: Hyperglycemia regulates cardiac K+ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways
verfasst von: Bence Hegyi
Johanna M. Borst
Logan R. J. Bailey
Erin Y. Shen
Austen J. Lucena
Manuel F. Navedo
Julie Bossuyt
Donald M. Bers
Publikationsdatum: 01.12.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology / Ausgabe 6/2020
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-020-00834-8

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Hyperglycemia regulates cardiac K⁺ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways

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