Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure

Circulation Research

Volumn 123, Issue 3, 2018, Pages 356-371

  Dey, Swati ^b   DeMazumder, Deeptankar ^a   Sidor, Agnieszka ^b   Brian Foster, D ^b   O'Rourke, Brian ^b  

^a UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Heart failure; Mitochondria; Phosphorylation; Proteomics; Reactive oxygen species; Ventricular fibrillation

Indexed keywords

ANGIOTENSIN RECEPTOR; ANTIOXIDANT; CALCIUM ION; CARRIER PROTEINS AND BINDING PROTEINS; HYDROGEN PEROXIDE; INWARDLY RECTIFYING POTASSIUM CHANNEL SUBUNIT KIR2.1; MITOCHONDRIALLY TARGETED ANTIOXIDANT; POTASSIUM CHANNEL; POTASSIUM CHANNEL KCNH4; POTASSIUM CHANNEL KCNQ1; PROTEIN ATP2A2; PROTEIN CACNA1C; PROTEOME; REACTIVE OXYGEN METABOLITE; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; UNCLASSIFIED DRUG; CALCIUM; MITOTEMPO; ORGANOPHOSPHORUS COMPOUND; PIPERIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CALCIUM TRANSPORT; CARDIAC MUSCLE CELL; CELLULAR DISTRIBUTION; CELLULAR STRESS SIGNAL; CLINICAL FEATURE; CONTROLLED STUDY; CYTOPLASM; DISPERSION; GUINEA PIG MODEL; HEART ELECTROPHYSIOLOGY; HEART FAILURE; HEART HYPERTROPHY; HEART LEFT VENTRICLE CONTRACTION; HEART MUSCLE POTENTIAL; HEART REPOLARIZATION; HEART VENTRICLE ARRHYTHMIA; HEART VENTRICLE EXTRASYSTOLE; HEART VENTRICLE HYPERTROPHY; IN VIVO STUDY; INCIDENCE; MAPK SIGNALING; METABOLISM; MITOCHONDRIAL DYNAMICS; MITOCHONDRION; NONHUMAN; OXIDATIVE STRESS; PHOSPHOPROTEOMICS; PHOSPHORYLATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN MODIFICATION; PROTEOMICS; QT PROLONGATION; SUDDEN CARDIAC DEATH; ANIMAL; COMPLICATION; DRUG EFFECT; GUINEA PIG; HEART MITOCHONDRION;

ANIMALS; ANTIOXIDANTS; CALCIUM; DEATH, SUDDEN, CARDIAC; GUINEA PIGS; HEART FAILURE; MITOCHONDRIA, HEART; ORGANOPHOSPHORUS COMPOUNDS; OXIDATIVE STRESS; PHOSPHORYLATION; PIPERIDINES; PROTEOME; REACTIVE OXYGEN SPECIES;

EID: 85054970157     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.118.312708     Document Type: Article

References (79)

1. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, Gheorghiade M. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63:1123-1133. doi: 10.1016/j.jacc.2013.11.053.
2. Mozaffarian D, Benjamin EJ, Go AS, et al; Writing Group Members; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-360. doi: 10.1161/CIR.0000000000000350.
3. Shen L, Jhund PS, Petrie MC, et al. Declining risk of sudden death in heart failure. N Engl J Med. 2017;377:41-51. doi: 10.1056/NEJMoa1609758.
4. Stecker EC, Vickers C, Waltz J, Socoteanu C, John BT, Mariani R, McAnulty JH, Gunson K, Jui J, Chugh SS. Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study. J Am Coll Cardiol. 2006;47:1161-1166. doi: 10.1016/j.jacc.2005.11.045.
5. Køber L, Thune JJ, Nielsen JC, et al; DANISH Investigators. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221-1230. doi: 10.1056/NEJMoa1608029.
6. Marín-García J, Akhmedov AT, Moe GW. Mitochondria in heart failure: the emerging role of mitochondrial dynamics. Heart Fail Rev. 2013;18:439-456. doi: 10.1007/s10741-012-9330-2.
7. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia-reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001;33:1065-1089. doi: 10.1006/jmcc.2001.1378.
8. Liu T, Takimoto E, Dimaano VL, DeMazumder D, Kettlewell S, Smith G, Sidor A, Abraham TP, O'Rourke B. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res. 2014;115:44-54. doi: 10.1161/CIRCRESAHA.115.303062.
9. Sovari AA, Rutledge CA, Jeong EM, Dolmatova E, Arasu D, Liu H, Vahdani N, Gu L, Zandieh S, Xiao L, Bonini MG, Duffy HS, Dudley SC Jr. Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circ Arrhythm Electrophysiol. 2013;6:623-631. doi: 10.1161/CIRCEP.112.976787.
10. Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 2005;115:500-508. doi: 10.1172/JCI24408.
11. Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT, MacCoss MJ, Rabinovitch PS. Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res. 2012;93:79-88. doi: 10.1093/cvr/cvr274.
12. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338-1347. doi: 10.1001/jama.293.11.1338.
13. Nightingale AK, Crilley JG, Pegge NC, Boehm EA, Mumford C, Taylor DJ, Styles P, Clarke K, Frenneaux MP. Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure. Eur J Heart Fail. 2007;9:287-291. doi: 10.1016/j.ejheart.2006.06.006.
14. Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24:1250-1261. doi: 10.1681/ASN.2012121216.
15. Brown DA, Hale SL, Baines CP, del Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Moukdar F, Shaikh SR, Fisher-Wellman KH, Neufer PD, Kloner RA. Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. J Cardiovasc Pharmacol Ther. 2014;19:121-132. doi: 10.1177/1074248413508003.
16. Sabbah HN, Gupta RC, Kohli S, Wang M, Hachem S, Zhang K. Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ Heart Fail. 2016;9:e002206. doi: 10.1161/CIRCHEARTFAILURE.115.002206.
17. Hortmann M, Robinson S, Mohr M, Mauler M, Stallmann D, Reinohl J, Duerschmied D, Peter K, Carr J, Gibson CM, Bode C, Ahrens I. The mitochondria-targeting peptide elamipretide diminishes circulating htra2 in st-segment elevation myocardial infarction [published online ahead of print May 1, 2017]. Eur Heart J Acute Cardiovasc Care. https://doi.org/10.1177/2048872617710789.
18. Daaboul Y, Korjian S, Weaver WD, et al. Relation of left ventricular mass and infarct size in anterior wall ST-segment elevation acute myocardial infarction (from the EMBRACE STEMI Clinical Trial). Am J Cardiol. 2016;118:625-631. doi: 10.1016/j.amjcard.2016.06.025.
19. Chakrabarti AK, Feeney K, Abueg C, Brown DA, Czyz E, Tendera M, Janosi A, Giugliano RP, Kloner RA, Weaver WD, Bode C, Godlewski J, Merkely B, Gibson CM. Rationale and design of the EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary percutaneous coronary intervention and stenting for ST-segment elevation myocardial infarction. Am Heart J. 2013;165:509.e7-514.e7. doi: 10.1016/j.ahj.2012.12.008.
20. Dietl A, Maack C. Targeting mitochondrial calcium handling and reactive oxygen species in heart failure. Curr Heart Fail Rep. 2017;14:338-349. doi: 10.1007/s11897-017-0347-7.
21. Foster DB, Liu T, Kammers K, O'Meally R, Yang N, Papanicolaou KN, Talbot CC Jr, Cole RN, O'Rourke B. Integrated omic analysis of a guinea pig model of heart failure and sudden cardiac death. J Proteome Res. 2016;15:3009-3028. doi: 10.1021/acs.jproteome.6b00149.
22. Meyer AJ, Dick TP. Fluorescent protein-based redox probes. Antioxid Redox Signal. 2010;13:621-650. doi: 10.1089/ars.2009.2948.
23. Dey S, Sidor A, O'Rourke B. Compartment-specific control of reactive oxygen species scavenging by antioxidant pathway enzymes. J Biol Chem. 2016;291:11185-11197. doi: 10.1074/jbc.M116.726968.
24. Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart. 2007;93:903-907. doi: 10.1136/hrt.2005.068270.
25. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909-950. doi: 10.1152/physrev.00026.2013.
26. Dikalov S. Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med. 2011;51:1289-1301. doi: 10.1016/j.freeradbiomed. 2011.06.033.
27. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017;86:715-748. doi: 10.1146/annurev-biochem-061516-045037.
28. Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Böhm M, O'Rourke B, Maack C. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation. 2010;121:1606-1613. doi: 10.1161/CIRCULATIONAHA.109.914911.
29. Dikalova AE, Kirilyuk IA, Dikalov SI. Antihypertensive effect of mitochondria-targeted proxyl nitroxides. Redox Biol. 2015;4:355-362. doi: 10.1016/j.redox.2014.12.012.
30. Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM. NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal. 2006;8:691-728. doi: 10.1089/ars.2006.8.691.
31. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977-984.
32. Berger RD. QT variability. J Electrocardiol. 2003;36(suppl):83-87.
33. DeMazumder D, Limpitikul WB, Dorante M, Dey S, Mukhopadhyay B, Zhang Y, Moorman JR, Cheng A, Berger RD, Guallar E, Jones SR, Tomaselli GF. Entropy of cardiac repolarization predicts ventricular arrhythmias and mortality in patients receiving an implantable cardio-verter-defibrillator for primary prevention of sudden death. Europace. 2016;18:1818-1828. doi: 10.1093/europace/euv399.
34. Rountree CB, Van Kirk CA, You H, Ding W, Dang H, VanGuilder HD, Freeman WM. Clinical application for the preservation of phospho-pro-teins through in-situ tissue stabilization. Proteome Sci. 2010;8:61. doi: 10.1186/1477-5956-8-61.
35. Kammers K, Cole RN, Tiengwe C, Ruczinski I. Detecting significant changes in protein abundance. EuPA Open Proteom. 2015;7:11-19. doi: 10.1016/j.euprot.2015.02.002.
36. Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T, Namba M. Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation. 1998;98:794-799.
37. Dhalla AK, Hill MF, Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol. 1996;28:506-514. doi: 10.1016/0735-1097(96)00140-4.
38. Date MO, Morita T, Yamashita N, Nishida K, Yamaguchi O, Higuchi Y, Hirotani S, Matsumura Y, Hori M, Tada M, Otsu K. The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model. J Am Coll Cardiol. 2002;39:907-912.
39. Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, dos Remedios C, Pritzker M, Hall JL, Garry DJ, Chen Y. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation. 2010;121:1474-1483. doi: 10.1161/CIRCULATIONAHA.109.906818.
40. Moens AL, Takimoto E, Tocchetti CG, et al. Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation. 2008;117:2626-2636. doi: 10.1161/CIRCULATIONAHA.107.737031.
41. Meagher E, Rader DJ. Antioxidant therapy and atherosclerosis: animal and human studies. Trends Cardiovasc Med. 2001;11:162-165.
42. Pasupathy S, Tavella R, Grover S, Raman B, Procter NEK, Du YT, Mahadavan G, Stafford I, Heresztyn T, Holmes A, Zeitz C, Arstall M, Selvanayagam J, Horowitz JD, Beltrame JF. Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]). Circulation. 2017;136:894-903. doi: 10.1161/CIRCULATIONAHA.117.027575.
43. Pasupathy S, Tavella R, Beltrame JF. Myocardial infarction with non-obstructive coronary arteries (MINOCA): the past, present, and future management. Circulation. 2017;135:1490-1493. doi: 10.1161/ CIRCULATIONAHA.117.027666.
44. Shekelle P, Morton S, Hardy ML. Effect of supplemental antioxidants vitamin C, vitamin E, and coenzyme Q10 for the prevention and treatment of cardiovascular disease. Evid Rep Technol Assess (Summ). 2003:1-3 No. 83, Report No.: 03-0043ISBN-10: 1-58763-090-7.
45. Sethi R, Takeda N, Nagano M, Dhalla NS. Beneficial effects of vitamin E treatment in acute myocardial infarction. J Cardiovasc Pharmacol Ther. 2000;5:51-58. doi: 10.1177/107424840000500107.
46. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2008;300:2123-2133. doi: 10.1001/jama.2008.600.
47. Marchioli R, Schweiger C, Levantesi G, Tavazzi L, Valagussa F. Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data. Lipids. 2001;36(suppl):S53-S63.
48. Durham JD, Caputo C, Dokko J, Zaharakis T, Pahlavan M, Keltz J, Dutka P, Marzo K, Maesaka JK, Fishbane S. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int. 2002;62:2202-2207. doi: 10.1046/j.1523-1755.2002.00673.x.
49. Reyes AJ, Leary WP. Allopurinol or oxypurinol in heart failure therapy - a promising new development or end of story? Cardiovasc Drugs Ther. 2005;19:311-313. doi: 10.1007/s10557-005-4971-1.
50. Doughan AK, Dikalov SI. Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis. Antioxid Redox Signal. 2007;9:1825-1836. doi: 10.1089/ars.2007.1693.
51. Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintrón M, Chen T, Marcinek DJ, Dorn GW II, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res. 2011;108:837-846. doi: 10.1161/CIRCRESAHA.110.232306.
52. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009;119:2789-2797. doi: 10.1161/ CIRCULATIONAHA.108.822403.
53. Kang PT, Chen CL, Ohanyan V, Luther DJ, Meszaros JG, Chilian WM, Chen YR. Overexpressing superoxide dismutase 2 induces a supernor-mal cardiac function by enhancing redox-dependent mitochondrial function and metabolic dilation. J Mol Cell Cardiol. 2015;88:14-28. doi: 10.1016/j.yjmcc.2015.09.001.
54. Anisimov VN, Egorov MV, Krasilshchikova MS, et al. Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents. Aging (Albany NY). 2011;3:1110-1119. doi: 10.18632/aging.100404.
55. Manskikh VN, Gancharova OS, Nikiforova AI, Krasilshchikova MS, Shabalina IG, Egorov MV, Karger EM, Milanovsky GE, Galkin II, Skulachev VP, Zinovkin RA. Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1. Histol Histopathol. 2015;30:353-360. doi: 10.14670/HH-30.353.
56. Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cochemé HM, Murphy MP, Dominiczak AF. Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension. 2009;54:322-328. doi: 10.1161/ HYPERTENSIONAHA.109.130351.
57. Rodriguez-Cuenca S, Cochemé HM, Logan A, et al. Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice. Free Radic Biol Med. 2010;48:161-172. doi: 10.1016/j.freeradbiomed.2009.10.039.
58. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005;19:1088-1095. doi: 10.1096/fj.05-3718com.
59. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171:2029-2050. doi: 10.1111/bph.12461.
60. Liu S, Soong Y, Seshan SV, Szeto HH. Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates mi-crovascular rarefaction, inflammation, and fibrosis. Am J Physiol Renal Physiol. 2014;306:F970-F980. doi: 10.1152/ajprenal.00697.2013.
61. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171:2017-2028. doi: 10.1111/ bph.12468.
62. Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. J Cardiovasc Pharmacol. 2014;64:543-553. doi: 10.1097/FJC.0000000000000155.
63. Dai DF, Chen T, Szeto H, Nieves-Cintrón M, Kutyavin V, Santana LF, Rabinovitch PS. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol. 2011;58:73-82. doi: 10.1016/j.jacc.2010.12.044.
64. Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, Harrison DG, Dikalov SI. Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res. 2010;107:106-116. doi: 10.1161/CIRCRESAHA.109.214601.
65. Namiecinski M, Pulaski L, Kochman A, Skolimowski J, Bartosz G, Metodiewa D. Cytotoxicity, cytoprotection and neurotoxicity of novel deprenyl-related propargylamines, stable nitroxide free radicals, in vitro and in vivo. In Vivo. 2004;18:171-180.
66. Kagan VE, Tyurina YY. Recycling and redox cycling of phenolic antioxidants. Ann NY Acad Sci. 1998;854:425-434.
67. Ni R, Cao T, Xiong S, Ma J, Fan GC, Lacefield JC, Lu Y, Le Tissier S, Peng T. Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol Med. 2016;90:12-23. doi: 10.1016/j.freeradbiomed.2015.11.013.
68. Jeong EM, Chung J, Liu H, Go Y, Gladstein S, Farzaneh-Far A, Lewandowski ED, Dudley SC, Jr. Role of mitochondrial oxidative stress in glucose tolerance, insulin resistance, and cardiac diastolic dysfunction. J Am Heart Assoc. 2016;5
69. Luo M, Guan X, Luczak ED, et al. Diabetes increases mortality after myocardial infarction by oxidizing camkii. J Clin Invest. 2013;123:1262-1274.
70. Holzem KM, Gomez JF, Glukhov AV, Madden EJ, Koppel AC, Ewald GA, Trenor B, Efimov IR. Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure. J Mol Cell Cardiol. 2016;96:82-92. doi: 10.1016/j.yjmcc.2015.06.008.
71. Liu R, Molkentin JD. Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs). J Mol Cell Cardiol. 2016;101:44-49. doi: 10.1016/j.yjmcc.2016.08.018.
72. Kehat I, Davis J, Tiburcy M, Accornero F, Saba-El-Leil MK, Maillet M, York AJ, Lorenz JN, Zimmermann WH, Meloche S, Molkentin JD. Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth. Circ Res. 2011;108:176-183. doi: 10.1161/CIRCRESAHA.110.231514.
73. Maillet M, Purcell NH, Sargent MA, York AJ, Bueno OF, Molkentin JD. DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem. 2008;283:31246-31255. doi: 10.1074/jbc.M806085200.
74. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 2000;19:6341-6350. doi: 10.1093/emboj/19.23.6341.
75. Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci USA. 2007;104:14074-14079. doi: 10.1073/pnas.0610906104.
76. Braz JC, Bueno OF, Liang Q, Wilkins BJ, Dai YS, Parsons S, Braunwart J, Glascock BJ, Klevitsky R, Kimball TF, Hewett TE, Molkentin JD. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest. 2003;111:1475-1486. doi: 10.1172/JCI17295.
77. Kaikkonen L, Magga J, Ronkainen VP, et al. p38α regulates SERCA2a function. J Mol Cell Cardiol. 2014;67:86-93. doi: 10.1016/j. yjmcc.2013.12.005.
78. Liu Q, Sargent MA, York AJ, Molkentin JD. ASK1 regulates cardiomyocyte death but not hypertrophy in transgenic mice. Circ Res. 2009;105:1110-1117. doi: 10.1161/CIRCRESAHA.109.200741.
79. Yamaguchi O, Higuchi Y, Hirotani S, et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc Natl Acad Sci USA. 2003;100:15883-15888. doi: 10.1073/pnas. 2136717100.