1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pharmacology and Toxicology
  4. Volume 63, 2023
  5. Article

Annual Review of Pharmacology and Toxicology

Volume 63, 2023

CaMKII as a Therapeutic Target in Cardiovascular Disease

Abstract

CaMKII (the multifunctional Ca2+ and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics.

Keyword(s): arrhythmias, calcium, CaMKII, cardiovascular disease, heart failure, kinase
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-051421-111814
2023-01-20
2024-05-02
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/63/1/annurev-pharmtox-051421-111814.html?itemId=/content/journals/10.1146/annurev-pharmtox-051421-111814&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Schulman H, Greengard P. 1978. Ca2+-dependent protein phosphorylation system in membranes from various tissues, and its activation by “calcium-dependent regulator.”. PNAS 75:5432–36
     [Google Scholar]
  2. 2.
    Tobimatsu T, Fujisawa H. 1989. Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs. J. Biol. Chem. 264:17907–12
     [Google Scholar]
  3. 3.
    Edman CF, Schulman H. 1994. Identification and characterization of δB-CaM kinase and δC-CaM kinase from rat heart, two new multifunctional Ca2+/calmodulin-dependent protein kinase isoforms. Biochim. Biophys. Acta 1221:89–101
     [Google Scholar]
  4. 4.
    Bayer KU, Lohler J, Schulman H, Harbers K. 1999. Developmental expression of the CaM kinase II isoforms: ubiquitous γ- and δ-CaM kinase II are the early isoforms and most abundant in the developing nervous system. Brain Res. Mol. Brain Res. 70:147–54
     [Google Scholar]
  5. 5.
    Lou LL, Schulman H. 1989. Distinct autophosphorylation sites sequentially produce autonomy and inhibition of the multifunctional Ca2+/calmodulin-dependent protein kinase. J. Neurosci. 9:2020–32
     [Google Scholar]
  6. 6.
    Miller SG, Patton BL, Kennedy MB. 1988. Sequences of autophosphorylation sites in neuronal type II CaM kinase that control Ca2+-independent activity. Neuron 1:593–604
     [Google Scholar]
  7. 7.
    Colbran RJ, Smith MK, Schworer CM, Fong YL, Soderling TR. 1989. Regulatory domain of calcium/calmodulin-dependent protein kinase II. Mechanism of inhibition and regulation by phosphorylation. J. Biol. Chem. 264:4800–4
     [Google Scholar]
  8. 8.
    Meyer T, Hanson PI, Stryer L, Schulman H. 1992. Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science 256:1199–202
     [Google Scholar]
  9. 9.
    Rich RC, Schulman H. 1998. Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 273:28424–29
     [Google Scholar]
  10. 10.
    Hanson PI, Meyer T, Stryer L, Schulman H. 1994. Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron 12:943–56
     [Google Scholar]
  11. 11.
    Erickson JR, Nichols CB, Uchinoumi H, Stein ML, Bossuyt J, Bers DM. 2015. S-nitrosylation induces both autonomous activation and inhibition of calcium/calmodulin-dependent protein kinase II δ. J. Biol. Chem. 290:25646–56
     [Google Scholar]
  12. 12.
    Coultrap SJ, Bayer KU. 2014. Nitric oxide induces Ca2+-independent activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII). J. Biol. Chem. 289:19458–65
     [Google Scholar]
  13. 13.
    Gutierrez DA, Fernandez-Tenorio M, Ogrodnik J, Niggli E. 2013. NO-dependent CaMKII activation during β-adrenergic stimulation of cardiac muscle. Cardiovasc. Res. 100:392–401
     [Google Scholar]
  14. 14.
    Zhu WZ, Wang SQ, Chakir K, Yang D, Zhang T et al. 2003. Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. J. Clin. Investig. 111:617–25
     [Google Scholar]
  15. 15.
    Hanson PI, Schulman H. 1992. Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed mutagenesis. J. Biol. Chem. 267:17216–24
     [Google Scholar]
  16. 16.
    Colbran RJ, Soderling TR. 1990. Calcium/calmodulin-independent autophosphorylation sites of calcium/calmodulin-dependent protein kinase II. Studies on the effect of phosphorylation of threonine 305/306 and serine 314 on calmodulin binding using synthetic peptides. J. Biol. Chem. 265:11213–19
     [Google Scholar]
  17. 17.
    Wagner S, Dantz C, Flebbe H, Azizian A, Sag CM et al. 2014. NADPH oxidase 2 mediates angiotensin II-dependent cellular arrhythmias via PKA and CaMKII. J. Mol. Cell. Cardiol. 75:206–15
     [Google Scholar]
  18. 18.
    Erickson JR, Pereira L, Wang L, Han G, Ferguson A et al. 2013. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502:372–76
     [Google Scholar]
  19. 19.
    Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV et al. 2011. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J. Clin. Investig. 121:3277–88
     [Google Scholar]
  20. 20.
    He BJ, Joiner ML, Singh MV, Luczak ED, Swaminathan PD et al. 2011. Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat. Med. 17:1610–18
     [Google Scholar]
  21. 21.
    Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J et al. 2008. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133:462–74
     [Google Scholar]
  22. 22.
    Konstantinidis K, Bezzerides VJ, Lai L, Isbell HM, Wei AC et al. 2020. MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII. J. Clin. Investig. 130:4663–78
     [Google Scholar]
  23. 23.
    Lu S, Liao Z, Lu X, Katschinski DM, Mercola M et al. 2020. Hyperglycemia acutely increases cytosolic reactive oxygen species via O-linked GlcNAcylation and CaMKII activation in mouse ventricular myocytes. Circ. Res. 126:e80–e96
     [Google Scholar]
  24. 24.
    Westenbrink BD, Ling H, Divakaruni AS, Gray CB, Zambon AC et al. 2015. Mitochondrial reprogramming induced by CaMKIIδ mediates hypertrophy decompensation. Circ. Res. 116:e28–39
     [Google Scholar]
  25. 25.
    Nishio S, Teshima Y, Takahashi N, Thuc LC, Saito S et al. 2012. Activation of CaMKII as a key regulator of reactive oxygen species production in diabetic rat heart. J. Mol. Cell. Cardiol. 52:1103–11
     [Google Scholar]
  26. 26.
    Hegyi B, Fasoli A, Ko CY, Van BW, Alim CC et al. 2021. CaMKII serine 280 O-GlcNAcylation links diabetic hyperglycemia to proarrhythmia. Circ. Res. 129:98–113
     [Google Scholar]
  27. 27.
    Mesubi OO, Rokita AG, Abrol N, Wu Y, Chen B et al. 2021. Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms. J. Clin. Investig. 131:e95747
     [Google Scholar]
  28. 28.
    Schworer CM, Rothblum LI, Thekkumkara TJ, Singer HA. 1993. Identification of novel isoforms of the delta subunit of Ca2+/calmodulin-dependent protein kinase II. Differential expression in rat brain and aorta. J. Biol. Chem. 268:14443–49
     [Google Scholar]
  29. 29.
    Zhang M, Gao H, Liu D, Zhong X, Shi X et al. 2019. CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair. Nat. Cell Biol. 21:1152–63
     [Google Scholar]
  30. 30.
    Mishra S, Gray CB, Miyamoto S, Bers DM, Brown JH. 2011. Location matters: clarifying the concept of nuclear and cytosolic CaMKII subtypes. Circ. Res. 109:1354–62
     [Google Scholar]
  31. 31.
    Srinivasan M, Edman CF, Schulman H. 1994. Alternative splicing introduces a nuclear localization signal that targets multifunctional CaM kinase to the nucleus. J. Cell Biol. 126:839–52
     [Google Scholar]
  32. 32.
    Carlson CR, Aronsen JM, Bergan-Dahl A, Moutty MC, Lunde M et al. 2022. AKAP18δ anchors and regulates CaMKII activity at phospholamban-SERCA2 and RYR. Circ. Res. 130:27–44
     [Google Scholar]
  33. 33.
    Luczak ED, Wu Y, Granger JM, Joiner MA, Wilson NR et al. 2020. Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy. Nat. Commun. 11:4416
     [Google Scholar]
  34. 34.
    Joiner ML, Koval OM, Li J, He BJ, Allamargot C et al. 2012. CaMKII determines mitochondrial stress responses in heart. Nature 491:269–73
     [Google Scholar]
  35. 35.
    Nguyen EK, Koval OM, Noble P, Broadhurst K, Allamargot C et al. 2018. CaMKII (Ca2+/calmodulin-dependent kinase II) in mitochondria of smooth muscle cells controls mitochondrial mobility, migration, and neointima formation. Arterioscler. Thromb. Vasc. Biol. 38:1333–45
     [Google Scholar]
  36. 36.
    Nickel AG, Kohlhaas M, Bertero E, Wilhelm D, Wagner M et al. 2020. CaMKII does not control mitochondrial Ca2+ uptake in cardiac myocytes. J. Physiol. 598:1361–76
     [Google Scholar]
  37. 37.
    Fieni F, Johnson DE, Hudmon A, Kirichok Y. 2014. Mitochondrial Ca2+ uniporter and CaMKII in heart. Nature 513:E1–2
     [Google Scholar]
  38. 38.
    Weinreuter M, Kreusser MM, Beckendorf J, Schreiter FC, Leuschner F et al. 2014. CaM kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury. EMBO Mol. Med. 6:1231–45
     [Google Scholar]
  39. 39.
    Zhang T, Guo T, Mishra S, Dalton ND, Kranias EG et al. 2010. Phospholamban ablation rescues sarcoplasmic reticulum Ca2+ handling but exacerbates cardiac dysfunction in CaMKIIδC transgenic mice. Circ. Res. 106:354–62
     [Google Scholar]
  40. 40.
    Davis FJ, Gupta M, Camoretti-Mercado B, Schwartz RJ, Gupta MP. 2003. Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4: implications in cardiac muscle gene regulation during hypertrophy. J. Biol. Chem. 278:20047–58
     [Google Scholar]
  41. 41.
    Saadatmand AR, Sramek V, Weber S, Finke D, Dewenter M et al. 2019. CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation. PNAS 116:22282–87
     [Google Scholar]
  42. 42.
    Awad S, Kunhi M, Little GH, Bai Y, An W et al. 2013. Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy. Nucleic Acids Res 41:7656–72
     [Google Scholar]
  43. 43.
    Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS et al. 2018. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase II δ signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation 138:2530–44
     [Google Scholar]
  44. 44.
    Gray CB, Suetomi T, Xiang S, Mishra S, Blackwood EA et al. 2017. CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α. J. Mol. Cell. Cardiol. 103:48–55
     [Google Scholar]
  45. 45.
    Ling H, Gray CB, Zambon AC, Grimm M, Gu Y et al. 2013. Ca2+/calmodulin-dependent protein kinase II δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κB. Circ. Res. 112:935–44
     [Google Scholar]
  46. 46.
    Singh MV, Kapoun A, Higgins L, Kutschke W, Thurman JM et al. 2009. Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart. J. Clin. Investig. 119:986–96
     [Google Scholar]
  47. 47.
    Kashiwase K, Higuchi Y, Hirotani S, Yamaguchi O, Hikoso S et al. 2005. CaMKII activates ASK1 and NF-κB to induce cardiomyocyte hypertrophy. Biochem. Biophys. Res. Commun. 327:136–42
     [Google Scholar]
  48. 48.
    Sun P, Enslen H, Myung PS, Maurer RA. 1994. Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev 8:2527–39
     [Google Scholar]
  49. 49.
    Wang P, Xu S, Xu J, Xin Y, Lu Y et al. 2022. Elevated MCU expression by CaMKIIδB limits pathological cardiac remodeling. Circulation 145:1067–83
     [Google Scholar]
  50. 50.
    Peng W, Zhang Y, Zheng M, Cheng H, Zhu W et al. 2010. Cardioprotection by CaMKII-δB is mediated by phosphorylation of heat shock factor 1 and subsequent expression of inducible heat shock protein 70. Circ. Res. 106:102–10
     [Google Scholar]
  51. 51.
    Anderson ME, Braun AP, Schulman H, Premack BA. 1994. Multifunctional Ca2+/calmodulin-dependent protein kinase mediates Ca2+-induced enhancement of the L-type Ca2+ current in rabbit ventricular myocytes. Circ. Res. 75:854–61
     [Google Scholar]
  52. 52.
    Thiel WH, Chen B, Hund TJ, Koval OM, Purohit A et al. 2008. Proarrhythmic defects in Timothy syndrome require calmodulin kinase II. Circulation 118:2225–34
     [Google Scholar]
  53. 53.
    Tessier S, Karczewski P, Krause EG, Pansard Y, Acar C et al. 1999. Regulation of the transient outward K+ current by Ca2+/calmodulin-dependent protein kinases II in human atrial myocytes. Circ. Res. 85:810–19
     [Google Scholar]
  54. 54.
    Li J, Marionneau C, Zhang R, Shah V, Hell JW et al. 2006. Calmodulin kinase II inhibition shortens action potential duration by upregulation of K+ currents. Circ. Res. 99:1092–99
     [Google Scholar]
  55. 55.
    Wu Y, Wang Q, Feng N, Granger JM, Anderson ME. 2019. Myocardial death and dysfunction after ischemia-reperfusion injury require CaMKIIδ oxidation. Sci. Rep. 9:9291
     [Google Scholar]
  56. 56.
    Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz L et al. 2006. Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J. Clin. Investig. 116:3127–38
     [Google Scholar]
  57. 57.
    Bengel P, Dybkova N, Tirilomis P, Ahmad S, Hartmann N et al. 2021. Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure. Nat. Commun. 12:6586
     [Google Scholar]
  58. 58.
    Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM. 2005. Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ. Res. 97:1314–22
     [Google Scholar]
  59. 59.
    Wehrens XHT, Lehnart SE, Reiken SR, Marks AR. 2004. Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ. Res. 94:e61–70
     [Google Scholar]
  60. 60.
    Wu Y, Roden DM, Anderson ME. 1999. Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. Circ. Res. 84:906–12
     [Google Scholar]
  61. 61.
    Simmerman HK, Collins JH, Theibert JL, Wegener AD, Jones LR. 1986. Sequence analysis of phospholamban. Identification of phosphorylation sites and two major structural domains. J. Biol. Chem. 261:13333–41
     [Google Scholar]
  62. 62.
    Scholten A, Preisinger C, Corradini E, Bourgonje VJ, Hennrich ML et al. 2013. Phosphoproteomics study based on in vivo inhibition reveals sites of calmodulin-dependent protein kinase II regulation in the heart. J. Am. Heart Assoc. 2:e000318
     [Google Scholar]
  63. 63.
    Hashimoto Y, Soderling TR. 1987. Calcium · calmodulin-dependent protein kinase II and calcium · phospholipid-dependent protein kinase activities in rat tissues assayed with a synthetic peptide. Arch. Biochem. Biophys. 252:418–25
     [Google Scholar]
  64. 64.
    Lou LL, Lloyd SJ, Schulman H. 1986. Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase by autophosphorylation: ATP modulates production of an autonomous enzyme. PNAS 83:9497–501
     [Google Scholar]
  65. 65.
    Kreusser MM, Lehmann LH, Keranov S, Hoting MO, Oehl U et al. 2014. Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. Circulation 130:1262–73
     [Google Scholar]
  66. 66.
    Lee S-JR, Escobedo-Lozoya Y, Szatmari EM, Yasuda R. 2009. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458:299–304
     [Google Scholar]
  67. 67.
    Takao K, Okamoto K, Nakagawa T, Neve RL, Nagai T et al. 2005. Visualization of synaptic Ca2+/calmodulin-dependent protein kinase II activity in living neurons. J. Neurosci. 25:3107–12
     [Google Scholar]
  68. 68.
    Bajar BT, Wang ES, Lam AJ, Kim BB, Jacobs CL et al. 2016. Improving brightness and photostability of green and red fluorescent proteins for live cell imaging and FRET reporting. Sci. Rep. 6:20889
     [Google Scholar]
  69. 69.
    Ardestani G, West MC, Maresca TJ, Fissore RA, Stratton MM. 2019. FRET-based sensor for CaMKII activity (FRESCA): a useful tool for assessing CaMKII activity in response to Ca2+ oscillations in live cells. J. Biol. Chem. 294:11876–91
     [Google Scholar]
  70. 70.
    Wang Q, Hernández-Ochoa EO, Viswanathan MC, Blum ID, Do DC et al. 2021. CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution. Nat. Commun. 12:3175
     [Google Scholar]
  71. 71.
    Tombes RM, Faison MO, Turbeville JM. 2003. Organization and evolution of multifunctional Ca2+/CaM-dependent protein kinase genes. Gene 322:17–31
     [Google Scholar]
  72. 72.
    Rothschild SC, Ingram SR, Lu FI, Thisse B, Thisse C et al. 2020. Genetic compensation of γ CaMKII, an evolutionarily conserved gene. Gene 742:144567
     [Google Scholar]
  73. 73.
    Lee SJ, Escobedo-Lozoya Y, Szatmari EM, Yasuda R. 2009. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458:299–304
     [Google Scholar]
  74. 74.
    Barria A, Malinow R. 2005. NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48:289–301
     [Google Scholar]
  75. 75.
    Opazo P, Labrecque S, Tigaret CM, Frouin A, Wiseman PW et al. 2010. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of Stargazin. Neuron 67:239–52
     [Google Scholar]
  76. 76.
    Tomita S, Stein V, Stocker TJ, Nicoll RA, Bredt DS. 2005. Bidirectional synaptic plasticity regulated by phosphorylation of Stargazin-like TARPs. Neuron 45:269–77
     [Google Scholar]
  77. 77.
    Frankland PW, O'Brien C, Ohno M, Kirkwood A, Silva AJ. 2001. α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411:309–13
     [Google Scholar]
  78. 78.
    Giese KP, Fedorov NB, Filipkowski RK, Silva AJ. 1998. Autophosphorylation at Thr286 of the α calcium-calmodulin kinase II in LTP and learning. Science 279:870–73
     [Google Scholar]
  79. 79.
    Silva AJ, Paylor R, Wehner JM, Tonegawa S. 1992. Impaired spatial learning in α-calcium-calmodulin kinase II mutant mice. Science 257:206–11
     [Google Scholar]
  80. 80.
    Chang JY, Parra-Bueno P, Laviv T, Szatmari EM, Lee SR, Yasuda R. 2017. CaMKII autophosphorylation is necessary for optimal integration of Ca2+ signals during LTP induction, but not maintenance. Neuron 94:800–8.e4
     [Google Scholar]
  81. 81.
    Murakoshi H, Shin ME, Parra-Bueno P, Szatmari EM, Shibata ACE, Yasuda R. 2017. Kinetics of endogenous CaMKII required for synaptic plasticity revealed by optogenetic kinase inhibitor. Neuron 94:37–47.e5
     [Google Scholar]
  82. 82.
    Buard I, Coultrap SJ, Freund RK, Lee YS, Dell'Acqua ML et al. 2010. CaMKII “autonomy” is required for initiating but not for maintaining neuronal long-term information storage. J. Neurosci. 30:8214–20
     [Google Scholar]
  83. 83.
    Cook SG, Buonarati OR, Coultrap SJ, Bayer KU. 2021. CaMKII holoenzyme mechanisms that govern the LTP versus LTD decision. Sci. Adv. 7:eabe2300
     [Google Scholar]
  84. 84.
    Vinogradova TM, Zhou YY, Bogdanov KY, Yang D, Kuschel M et al. 2000. Sinoatrial node pacemaker activity requires Ca2+/calmodulin-dependent protein kinase II activation. Circ. Res. 87:760–67
     [Google Scholar]
  85. 85.
    Sag CM, Wagner S, Maier LS. 2013. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic. Biol. Med. 63:338–49
     [Google Scholar]
  86. 86.
    Wu Y, Gao Z, Chen B, Koval OM, Singh MV et al. 2009. Calmodulin kinase II is required for fight or flight sinoatrial node physiology. PNAS 106:5972–77
     [Google Scholar]
  87. 87.
    Chang BH, Mukherji S, Soderling TR. 1998. Characterization of a calmodulin kinase II inhibitor protein in brain. PNAS 95:10890–95
     [Google Scholar]
  88. 88.
    Prasad AM, Morgan DA, Nuno DW, Ketsawatsomkron P, Bair TB et al. 2015. Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function. J. Am. Heart Assoc. 4:e001949
     [Google Scholar]
  89. 89.
    Prasad AM, Nuno DW, Koval OM, Ketsawatsomkron P, Li W et al. 2013. Differential control of calcium homeostasis and vascular reactivity by Ca2+/calmodulin-dependent kinase II. Hypertension 62:434–41
     [Google Scholar]
  90. 90.
    Kobayashi T, Nemoto S, Ishida K, Taguchi K, Matsumoto T, Kamata K. 2012. Involvement of CaM kinase II in the impairment of endothelial function and eNOS activity in aortas of type 2 diabetic rats. Clin. Sci. 123:375–86
     [Google Scholar]
  91. 91.
    Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R. 2001. Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ. Res. 88:E68–75
     [Google Scholar]
  92. 92.
    Li W, Li H, Sanders PN, Mohler PJ, Backs J et al. 2011. The multifunctional Ca2+/calmodulin-dependent kinase II δ (CaMKIIδ) controls neointima formation after carotid ligation and vascular smooth muscle cell proliferation through cell cycle regulation by p21. J. Biol. Chem. 286:7990–99
     [Google Scholar]
  93. 93.
    Pfleiderer PJ, Lu KK, Crow MT, Keller RS, Singer HA. 2004. Modulation of vascular smooth muscle cell migration by calcium/calmodulin-dependent protein kinase II-δ2. Am. J. Physiol. Cell Physiol. 286:C1238–45
     [Google Scholar]
  94. 94.
    Scott JA, Klutho PJ, El Accaoui R, Nguyen E, Venema AN et al. 2013. The multifunctional Ca2+/calmodulin-dependent kinase IIδ (CaMKIIδ) regulates arteriogenesis in a mouse model of flow-mediated remodeling. PLOS ONE 8:e71550
     [Google Scholar]
  95. 95.
    Scott JA, Xie L, Li H, Li W, He JB et al. 2012. The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9. Am. J. Physiol. Heart Circ. Physiol. 302:H1953–64
     [Google Scholar]
  96. 96.
    Lu XZ, Bi XY, He X, Zhao M, Xu M et al. 2015. Activation of M3 cholinoceptors attenuates vascular injury after ischaemia/reperfusion by inhibiting the Ca2+/calmodulin-dependent protein kinase II pathway. Br. J. Pharmacol. 172:5619–33
     [Google Scholar]
  97. 97.
    McCluskey C, Mooney L, Paul A, Currie S 2019. Compromised cardiovascular function in aged rats corresponds with increased expression and activity of calcium/calmodulin dependent protein kinase IIδ in aortic endothelium. Vascul. Pharmacol.118–119106560
     [Google Scholar]
  98. 98.
    Seidlmayer LK, Mages C, Berbner A, Eder-Negrin P, Arias-Loza PA et al. 2019. Mitofusin 2 is essential for IP3-mediated SR/mitochondria metabolic feedback in ventricular myocytes. Front. Physiol. 10:733
     [Google Scholar]
  99. 99.
    Federico M, Zavala M, Vico T, Lopez S, Portiansky E et al. 2021. CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling. Sci. Rep. 11:20025
     [Google Scholar]
  100. 100.
    Joseph LC, Reyes MV, Homan EA, Gowen B, Avula UMR et al. 2021. The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet. Sci. Rep. 11:17808
     [Google Scholar]
  101. 101.
    Rose AJ, Alsted TJ, Kobbero JB, Richter EA. 2007. Regulation and function of Ca2+-calmodulin-dependent protein kinase II of fast-twitch rat skeletal muscle. J. Physiol. 580:993–1005
     [Google Scholar]
  102. 102.
    Rose AJ, Hargreaves M. 2003. Exercise increases Ca2+-calmodulin-dependent protein kinase II activity in human skeletal muscle. J. Physiol. 553:303–9
     [Google Scholar]
  103. 103.
    Dulhunty AF, Laver D, Curtis SM, Pace S, Haarmann C, Gallant EM. 2001. Characteristics of irreversible ATP activation suggest that native skeletal ryanodine receptors can be phosphorylated via an endogenous CaMKII. Biophys. J. 81:3240–52
     [Google Scholar]
  104. 104.
    Witczak CA, Jessen N, Warro DM, Toyoda T, Fujii N et al. 2010. CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 298:E1150–60
     [Google Scholar]
  105. 105.
    Fluck M, Booth FW, Waxham MN. 2000. Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. Biochem. Biophys. Res. Commun. 270:488–94
     [Google Scholar]
  106. 106.
    Liu Y, Randall WR, Schneider MF. 2005. Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle. J. Cell Biol. 168:887–97
     [Google Scholar]
  107. 107.
    Eigler T, Zarfati G, Amzallag E, Sinha S, Segev N et al. 2021. ERK1/2 inhibition promotes robust myotube growth via CaMKII activation resulting in myoblast-to-myotube fusion. Dev. Cell 56:3349–63.e6
     [Google Scholar]
  108. 108.
    Backs J, Stein P, Backs T, Duncan FE, Grueter CE et al. 2010. The γ isoform of CaM kinase II controls mouse egg activation by regulating cell cycle resumption. PNAS 107:81–86
     [Google Scholar]
  109. 109.
    Chang HY, Minahan K, Merriman JA, Jones KT. 2009. Calmodulin-dependent protein kinase gamma 3 (CamKIIγ3) mediates the cell cycle resumption of metaphase II eggs in mouse. Development 136:4077–81
     [Google Scholar]
  110. 110.
    Saunders CM, Larman MG, Parrington J, Cox LJ, Royse J et al. 2002. PLCζ: a sperm-specific trigger of Ca2+ oscillations in eggs and embryo development. Development 129:3533–44
     [Google Scholar]
  111. 111.
    Madgwick S, Levasseur M, Jones KT. 2005. Calmodulin-dependent protein kinase II, and not protein kinase C, is sufficient for triggering cell-cycle resumption in mammalian eggs. J. Cell Sci. 118:3849–59
     [Google Scholar]
  112. 112.
    Nixon VL, Levasseur M, McDougall A, Jones KT. 2002. Ca2+ oscillations promote APC/C-dependent cyclin B1 degradation during metaphase arrest and completion of meiosis in fertilizing mouse eggs. Curr. Biol. 12:746–50
     [Google Scholar]
  113. 113.
    Matsumoto Y, Maller JL. 2002. Calcium, calmodulin, and CaMKII requirement for initiation of centrosome duplication in Xenopus egg extracts. Science 295:499–502
     [Google Scholar]
  114. 114.
    Zhang T, Maier LS, Dalton ND, Miyamoto S, Ross J Jr. et al. 2003. The δC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ. Res. 92:912–19
     [Google Scholar]
  115. 115.
    Sossalla S, Fluschnik N, Schotola H, Ort KR, Neef S et al. 2010. Inhibition of elevated Ca2+/calmodulin-dependent protein kinase II improves contractility in human failing myocardium. Circ. Res. 107:1150–61
     [Google Scholar]
  116. 116.
    Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N et al. 2010. CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ. Res. 106:1134–44
     [Google Scholar]
  117. 117.
    Singh MV, Swaminathan PD, Luczak ED, Kutschke W, Weiss RM, Anderson ME. 2012. MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction. J. Mol. Cell. Cardiol. 52:1135–44
     [Google Scholar]
  118. 118.
    Zhang T, Zhang Y, Cui M, Jin L, Wang Y et al. 2016. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat. Med. 22:175–82
     [Google Scholar]
  119. 119.
    Yang Y, Zhu WZ, Joiner ML, Zhang R, Oddis CV et al. 2006. Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo. Am. J. Physiol. Heart Circ. Physiol. 291:H3065–75
     [Google Scholar]
  120. 120.
    Dewenter M, Neef S, Vettel C, Lammle S, Beushausen C et al. 2017. Calcium/calmodulin-dependent protein kinase II activity persists during chronic β-adrenoceptor blockade in experimental and human heart failure. Circ. Heart Fail. 10:e003840
     [Google Scholar]
  121. 121.
    Hagemann D, Bohlender J, Hoch B, Krause EG, Karczewski P. 2001. Expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in rats with hypertensive cardiac hypertrophy. Mol. Cell Biochem. 220:69–76
     [Google Scholar]
  122. 122.
    Hempel P, Hoch B, Bartel S, Karczewski P. 2002. Hypertrophic phenotype of cardiac calcium/calmodulin-dependent protein kinase II is reversed by angiotensin converting enzyme inhibition. Basic Res. Cardiol. 97:Suppl. 1I96–101
     [Google Scholar]
  123. 123.
    Gruver CL, DeMayo F, Goldstein MA, Means AR. 1993. Targeted developmental overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology 133:376–88
     [Google Scholar]
  124. 124.
    Zhang T, Johnson EN, Gu Y, Morissette MR, Sah VP et al. 2002. The cardiac-specific nuclear δB isoform of Ca2+/calmodulin-dependent protein kinase II induces hypertrophy and dilated cardiomyopathy associated with increased protein phosphatase 2A activity. J. Biol. Chem. 277:1261–67
     [Google Scholar]
  125. 125.
    Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE et al. 2005. Calmodulin kinase II inhibition protects against structural heart disease. Nat. Med. 11:409–17
     [Google Scholar]
  126. 126.
    Khoo MS, Li J, Singh MV, Yang Y, Kannankeril P et al. 2006. Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy. Circulation 114:1352–59
     [Google Scholar]
  127. 127.
    Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH et al. 2009. The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. PNAS 106:2342–47
     [Google Scholar]
  128. 128.
    Ling H, Zhang T, Pereira L, Means CK, Cheng H et al. 2009. Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J. Clin. Investig. 119:1230–40
     [Google Scholar]
  129. 129.
    Mesubi OO, Anderson ME. 2016. Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal. Cardiovasc. Res. 109:542–57
     [Google Scholar]
  130. 130.
    Grygorczyk R, Hanke-Baier P, Schwarz W, Passow H. 1989. Measurement of erythroid band 3 protein-mediated anion transport in mRNA-injected oocytes of Xenopus laevis. Methods Enzymol 173:453–66
     [Google Scholar]
  131. 131.
    Gomes JA, Kang PS, Matheson M, Gough WB Jr., El-Sherif N. 1981. Coexistence of sick sinus rhythm and atrial flutter-fibrillation. Circulation 63:80–86
     [Google Scholar]
  132. 132.
    Yan J, Zhao W, Thomson JK, Gao X, DeMarco DM et al. 2018. Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis. Circ. Res. 122:821–35
     [Google Scholar]
  133. 133.
    Yang KC, Dudley SC Jr. 2013. Oxidative stress and atrial fibrillation: finding a missing piece to the puzzle. Circulation 128:1724–26
     [Google Scholar]
  134. 134.
    He BJ, Anderson ME. 2013. Aldosterone and cardiovascular disease: the heart of the matter. Trends Endocrinol. Metab. 24:21–30
     [Google Scholar]
  135. 135.
    Nattel S. 2002. New ideas about atrial fibrillation 50 years on. Nature 415:219–26
     [Google Scholar]
  136. 136.
    Workman AJ. 2010. Cardiac adrenergic control and atrial fibrillation. Naunyn Schmiedebergs Arch. Pharmacol. 381:235–49
     [Google Scholar]
  137. 137.
    Mudd JO, Kass DA 2008. Tackling heart failure in the twenty-first century. Nature 451:919–28
     [Google Scholar]
  138. 138.
    Swaminathan PD, Purohit A, Hund TJ, Anderson ME. 2012. Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias. Circ. Res. 110:1661–77
     [Google Scholar]
  139. 139.
    El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M et al. 2006. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation 114:670–80
     [Google Scholar]
  140. 140.
    Bers DM, Grandi E. 2009. Calcium/calmodulin-dependent kinase II regulation of cardiac ion channels. J. Cardiovasc. Pharmacol. 54:180–87
     [Google Scholar]
  141. 141.
    Cheng H, Lederer WJ, Cannell MB. 1993. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262:740–44
     [Google Scholar]
  142. 142.
    Liu Z, Finet JE, Wolfram JA, Anderson ME, Ai X, Donahue JK 2019. Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure. Heart Rhythm 16:1080–88
     [Google Scholar]
  143. 143.
    Purohit A, Rokita AG, Guan X, Chen B, Koval OM et al. 2013. Oxidized Ca2+/calmodulin-dependent protein kinase II triggers atrial fibrillation. Circulation 128:1748–57
     [Google Scholar]
  144. 144.
    Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ et al. 2009. Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J. Clin. Investig. 119:1940–51
     [Google Scholar]
  145. 145.
    Bezzerides VJ, Caballero A, Wang S, Ai Y, Hylind RJ et al. 2019. Gene therapy for catecholaminergic polymorphic ventricular tachycardia by inhibition of Ca2+/calmodulin-dependent kinase II. Circulation 140:405–19
     [Google Scholar]
  146. 146.
    Liu N, Ruan Y, Denegri M, Bachetti T, Li Y et al. 2011. Calmodulin kinase II inhibition prevents arrhythmias in RyR2R4496C+/− mice with catecholaminergic polymorphic ventricular tachycardia. J. Mol. Cell. Cardiol. 50:214–22
     [Google Scholar]
  147. 147.
    Wu Y, MacMillan LB, McNeill RB, Colbran RJ, Anderson ME. 1999. CaM kinase augments cardiac L-type Ca2+ current: a cellular mechanism for long Q-T arrhythmias. Am. J. Physiol. 276:H2168–78
     [Google Scholar]
  148. 148.
    Anderson ME, Braun AP, Wu Y, Lu T, Wu Y et al. 1998. KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. J. Pharmacol. Exp. Ther. 287:996–1006
     [Google Scholar]
  149. 149.
    Liu X, Wang S, Guo X, Li Y, Ogurlu R et al. 2021. Increased reactive oxygen species-mediated Ca2+/calmodulin-dependent protein kinase II activation contributes to calcium handling abnormalities and impaired contraction in Barth syndrome. Circulation 143:1894–911
     [Google Scholar]
  150. 150.
    Wang Q, Quick AP, Cao S, Reynolds J, Chiang DY et al. 2018. Oxidized CaMKII (Ca2+/calmodulin-dependent protein kinase II) is essential for ventricular arrhythmia in a mouse model of Duchenne muscular dystrophy. Circ. Arrhythm. Electrophysiol. 11:e005682
     [Google Scholar]
  151. 151.
    DeGrande S, Nixon D, Koval O, Curran JW, Wright P et al. 2012. CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome. Heart Rhythm 9:2034–41
     [Google Scholar]
  152. 152.
    Ho HT, Liu B, Snyder JS, Lou Q, Brundage EA et al. 2014. Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides. Cardiovasc. Res. 101:165–74
     [Google Scholar]
  153. 153.
    Mustroph J, Wagemann O, Lebek S, Tarnowski D, Ackermann J et al. 2018. SR Ca2+-leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure. J. Mol. Cell. Cardiol. 116:81–90
     [Google Scholar]
  154. 154.
    van Oort RJ, McCauley MD, Dixit SS, Pereira L, Yang Y et al. 2010. Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation 122:2669–79
     [Google Scholar]
  155. 155.
    Fischer TH, Herting J, Tirilomis T, Renner A, Neef S et al. 2013. Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology. Circulation 128:970–81
     [Google Scholar]
  156. 156.
    Fischer TH, Eiringhaus J, Dybkova N, Forster A, Herting J et al. 2014. Ca2+/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca2+ leak in human ischaemic and dilated cardiomyopathy. Eur. J. Heart Fail. 16:1292–300
     [Google Scholar]
  157. 157.
    Pabel S, Knierim M, Stehle T, Alebrand F, Paulus M et al. 2022. Effects of atrial fibrillation on the human ventricle. Circ. Res. 130:7994–1010
     [Google Scholar]
  158. 158.
    Feng N, Anderson ME. 2017. CaMKII is a nodal signal for multiple programmed cell death pathways in heart. J. Mol. Cell. Cardiol. 103:102–9
     [Google Scholar]
  159. 159.
    Vila-Petroff M, Salas MA, Said M, Valverde CA, Sapia L et al. 2007. CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia-reperfusion injury. Cardiovasc. Res. 73:689–98
     [Google Scholar]
  160. 160.
    Sumi M, Kiuchi K, Ishikawa T, Ishii A, Hagiwara M et al. 1991. The newly synthesized selective Ca2+ calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells. Biochem. Biophys. Res. Commun. 181:968–75
     [Google Scholar]
  161. 161.
    Anderson ME, Braun AP, Wu Y, Lu T, Wu Y et al. 1998. KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. J. Pharmacol. Exp. Ther. 287:996–1006
     [Google Scholar]
  162. 162.
    Li G, Hidaka H, Wollheim CB. 1992. Inhibition of voltage-gated Ca2+ channels and insulin secretion in HIT cells by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62: comparison with antagonists of calmodulin and L-type Ca2+ channels. Mol. Pharmacol. 42:489–88
     [Google Scholar]
  163. 163.
    Hegyi B, Chen-Izu Y, Jian Z, Shimkunas R, Izu LT, Banyasz T. 2015. KN-93 inhibits IKr in mammalian cardiomyocytes. J. Mol. Cell. Cardiol. 89:173–76
     [Google Scholar]
  164. 164.
    Rezazadeh S, Claydon TW, Fedida D. 2006. KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine), a calcium/calmodulin-dependent protein kinase II inhibitor, is a direct extracellular blocker of voltage-gated potassium channels. J. Pharmacol. Exp. Ther. 317:292–99
     [Google Scholar]
  165. 165.
    Gao Y, Davies SP, Augustin M, Woodward A, Patel UA et al. 2013. A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J. 451:313–28
     [Google Scholar]
  166. 166.
    Wong MH, Samal AB, Lee M, Vlach J, Novikov N et al. 2019. The KN-93 molecule inhibits calcium/calmodulin-dependent protein kinase II (CaMKII) activity by binding to Ca2+/CaM. J. Mol. Biol. 431:1440–59
     [Google Scholar]
  167. 167.
    Johnson CN, Pattanayek R, Potet F, Rebbeck RT, Blackwell DJ et al. 2019. The CaMKII inhibitor KN93-calmodulin interaction and implications for calmodulin tuning of NaV1. 5 and RyR2 function. Cell Calcium 82:102063
     [Google Scholar]
  168. 168.
    Neef S, Steffens A, Pellicena P, Mustroph J, Lebek S et al. 2018. Improvement of cardiomyocyte function by a novel pyrimidine-based CaMKII-inhibitor. J. Mol. Cell. Cardiol. 115:73–81
     [Google Scholar]
  169. 169.
    Lebek S, Plößl A, Baier M, Mustroph J, Tarnowski D et al. 2018. The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity. J. Mol. Cell. Cardiol. 118:159–68
     [Google Scholar]
  170. 170.
    Beauverger P, Ozoux M-L, Bégis G, Glénat V, Briand V et al. 2019. Reversion of cardiac dysfunction by a novel orally available calcium/calmodulin-dependent protein kinase II inhibitor, RA306, in a genetic model of dilated cardiomyopathy. Cardiovasc. Res. 116:329–38
     [Google Scholar]
  171. 171.
    Mustroph J, Drzymalski M, Baier M, Pabel S, Biedermann A et al. 2020. The oral Ca/calmodulin-dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure. ESC Heart Fail 7:2871–83
     [Google Scholar]
  172. 172.
    Westra J, Brouwer E, van Roosmalen IA, Doornbos-van der Meer B, van Leeuwen MA et al. 2010. Expression and regulation of HIF-1alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. BMC Musculoskelet. Disord. 11:61
     [Google Scholar]
  173. 173.
    Neef S, Mann C, Zwenger A, Dybkova N, Maier LS. 2017. Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability. Basic Res. Cardiol. 112:45
     [Google Scholar]
  174. 174.
    Lim NR, Thomas CJ, Silva LS, Yeap YY, Yap S et al. 2013. Cardioprotective 3′,4′-dihydroxyflavonol attenuation of JNK and p38(MAPK) signalling involves CaMKII inhibition. Biochem. J. 456:149–61
     [Google Scholar]
  175. 175.
    Boyle AJ, Schultz C, Selvanayagam JB, Moir S, Kovacs R et al. 2021. Calcium/calmodulin-dependent protein kinase II δ inhibition and ventricular remodeling after myocardial infarction: a randomized clinical trial. JAMA Cardiol 6:762–68
     [Google Scholar]
  176. 176.
    Anderson ME. 2021. To be or not to be a CaMKII inhibitor?. JAMA Cardiol 6:769–70
     [Google Scholar]
  177. 177.
    Chang BH, Mukherji S, Soderling TR. 2001. Calcium/calmodulin-dependent protein kinase II inhibitor protein: localization of isoforms in rat brain. Neuroscience 102:767–77
     [Google Scholar]
  178. 178.
    Coultrap SJ, Bayer KU. 2011. Improving a natural CaMKII inhibitor by random and rational design. PLOS ONE 6:e25245
     [Google Scholar]
  179. 179.
    Deng G, Orfila JE, Dietz RM, Moreno-Garcia M, Rodgers KM et al. 2017. Autonomous CaMKII activity as a drug target for histological and functional neuroprotection after resuscitation from cardiac arrest. Cell Rep 18:1109–17
     [Google Scholar]
  180. 180.
    Ahmed ME, Dong Y, Lu Y, Tucker D, Wang R, Zhang Q. 2017. Beneficial effects of a CaMKIIα inhibitor TatCN21 peptide in global cerebral ischemia. J. Mol. Neurosci. 61:42–51
     [Google Scholar]
  181. 181.
    Braun AP, Schulman H. 1995. A non-selective cation current activated via the multifunctional Ca2+-calmodulin-dependent protein kinase in human epithelial cells. J. Physiol. 488:137–55
     [Google Scholar]
  182. 182.
    Ishida A, Kameshita I, Okuno S, Kitani T, Fujisawa H. 1995. A novel highly specific and potent inhibitor of calmodulin-dependent protein kinase II. Biochem. Biophys. Res. Commun. 212:806–12
     [Google Scholar]
  183. 183.
    Hanson PI, Kapiloff MS, Lou LL, Rosenfeld MG, Schulman H. 1989. Expression of a multifunctional Ca2+/calmodulin-dependent protein kinase and mutational analysis of its autoregulation. Neuron 3:59–70
     [Google Scholar]
  184. 184.
    Miragoli M, Ceriotti P, Iafisco M, Vacchiano M, Salvarani N et al. 2018. Inhalation of peptide-loaded nanoparticles improves heart failure. Sci. Transl. Med. 10:eaan6205
     [Google Scholar]
  185. 185.
    Shin M, Lee HA, Lee M, Shin Y, Song JJ et al. 2018. Targeting protein and peptide therapeutics to the heart via tannic acid modification. Nat. Biomed. Eng. 2:304–17
     [Google Scholar]
  186. 186.
    Gennemark P, Walter K, Clemmensen N, Rekic D, Nilsson CAM et al. 2021. An oral antisense oligonucleotide for PCSK9 inhibition. Sci. Transl. Med. 13:eabe9117
     [Google Scholar]
  187. 187.
    Geary RS, Norris D, Yu R, Bennett CF 2015. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv. Drug Deliv. Rev. 87:46–51
     [Google Scholar]
  188. 188.
    Roberts TC, Langer R, Wood MJA. 2020. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19:673–94
     [Google Scholar]
  189. 189.
    Yeh T-yT, Yeap XY, Mullick AE 2020. Downregulation of Ca2+/calmodulin-dependent protein kinase type II δ in the heart by antisense oligonucleotides mitigates development of post-infarct ventricular arrhythmias. Circ. Res. 127:A438
     [Google Scholar]
  190. 190.
    Koblan LW, Erdos MR, Wilson C, Cabral WA, Levy JM et al. 2021. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice. Nature 589:608–14
     [Google Scholar]
  191. 191.
    Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN. 2014. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345:1184–88
     [Google Scholar]
  192. 192.
    Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE et al. 2021. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 593:429–34
     [Google Scholar]
  193. 193.
    Johansen AK, Molenaar B, Versteeg D, Leitoguinho AR, Demkes C et al. 2017. Postnatal cardiac gene editing using CRISPR/Cas9 with AAV9-mediated delivery of short guide RNAs results in mosaic gene disruption. Circ. Res. 121:1168–81
     [Google Scholar]
  194. 194.
    Schoger E, Carroll KJ, Iyer LM, McAnally JR, Tan W et al. 2020. CRISPR-mediated activation of endogenous gene expression in the postnatal heart. Circ. Res. 126:6–24
     [Google Scholar]
  195. 195.
    Wang P, Mei F, Hu J, Zhu M, Qi H et al. 2017. PTENα modulates CaMKII signaling and controls contextual fear memory and spatial learning. Cell Rep 19:2627–41
     [Google Scholar]
  196. 196.
    Strack S, Barban MA, Wadzinski BE, Colbran RJ. 1997. Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J. Neurochem. 68:2119–28
     [Google Scholar]
  197. 197.
    Fukunaga K, Kobayashi T, Tamura S, Miyamoto E. 1993. Dephosphorylation of autophosphorylated Ca2+/calmodulin-dependent protein kinase II by protein phosphatase 2C. J. Biol. Chem. 268:133–37
     [Google Scholar]
  198. 198.
    Leurs U, Klein AB, McSpadden ED, Griem-Krey N, Solbak SMO et al. 2021. GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain. PNAS 118:e2108079118
     [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-051421-111814
Loading
CaMKII as a Therapeutic Target in Cardiovascular Disease
Annual Review of Pharmacology and Toxicology 63, 249 (2023); https://doi.org/10.1146/annurev-pharmtox-051421-111814
/content/journals/10.1146/annurev-pharmtox-051421-111814
/content/journals/10.1146/annurev-pharmtox-051421-111814
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error