Physiological and Unappreciated Roles of CaMKII in the Heart

Overview

Journal Basic Res Cardiol

Specialty Cardiology & Vascular Diseases

Date 2018 Jun 16

PMID 29905892

Citations 72

Authors

Jan Beckendorf

Maarten M G van den Hoogenhof

Johannes Backs

Affiliations

Soon will be listed here.

Abstract

In the cardiomyocyte, CaMKII has been identified as a nodal influencer of excitation-contraction and also excitation-transcription coupling. Its activity can be regulated in response to changes in intracellular calcium content as well as after several post-translational modifications. Some of the effects mediated by CaMKII may be considered adaptive, while effects of sustained CaMKII activity may turn into the opposite and are detrimental to cardiac integrity and function. As such, CaMKII has long been noted as a promising target for pharmacological inhibition, but the ubiquitous nature of CaMKII has made it difficult to target CaMKII specifically where it is detrimental. In this review, we provide a brief overview of the physiological and pathophysiological properties of CaMKII signaling, but we focus on the physiological and adaptive functions of CaMKII. Furthermore, special consideration is given to the emerging role of CaMKII as a mediator of inflammatory processes in the heart.

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References

Weinreuter M, Kreusser M, Beckendorf J, Schreiter F, Leuschner F, Lehmann L . CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury. EMBO Mol Med. 2014; 6(10):1231-45. PMC: 4287929. DOI: 10.15252/emmm.201403848. View

Ozcan L, Wong C, Li G, Xu T, Pajvani U, Park S . Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab. 2012; 15(5):739-51. PMC: 3348356. DOI: 10.1016/j.cmet.2012.03.002. View

Wu Y, Valdivia H, Wehrens X, Anderson M . A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol. 2016; 9(2):e003180. PMC: 4755317. DOI: 10.1161/CIRCEP.115.003180. View

Neef S, Sag C, Daut M, Baumer H, Grefe C, El-Armouche A . While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice. J Mol Cell Cardiol. 2013; 59:107-16. PMC: 3738196. DOI: 10.1016/j.yjmcc.2013.02.014. View

Ozcan L, Cristina de Souza J, Harari A, Backs J, Olson E, Tabas I . Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metab. 2013; 18(6):803-15. PMC: 3863383. DOI: 10.1016/j.cmet.2013.10.011. View

Liu X, Yao M, Li N, Wang C, Zheng Y, Cao X . CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages. Blood. 2008; 112(13):4961-70. DOI: 10.1182/blood-2008-03-144022. View

Eefting F, Rensing B, Wigman J, Pannekoek W, Liu W, Cramer M . Role of apoptosis in reperfusion injury. Cardiovasc Res. 2004; 61(3):414-26. DOI: 10.1016/j.cardiores.2003.12.023. View

Mattiazzi A, Bassani R, Escobar A, Palomeque J, Valverde C, Vila Petroff M . Chasing cardiac physiology and pathology down the CaMKII cascade. Am J Physiol Heart Circ Physiol. 2015; 308(10):H1177-91. PMC: 4436987. DOI: 10.1152/ajpheart.00007.2015. View

Mattiazzi A, Vittone L, Mundina-Weilenmann C . Ca2+/calmodulin-dependent protein kinase: a key component in the contractile recovery from acidosis. Cardiovasc Res. 2007; 73(4):648-56. DOI: 10.1016/j.cardiores.2006.12.002. View

10.

Solaro R . Sarcomere control mechanisms and the dynamics of the cardiac cycle. J Biomed Biotechnol. 2010; 2010:105648. PMC: 2866969. DOI: 10.1155/2010/105648. View

11.

Wright S, Schellenberger U, Ji L, Wang H, Larrick J . Calmodulin-dependent protein kinase II mediates signal transduction in apoptosis. FASEB J. 1997; 11(11):843-9. DOI: 10.1096/fasebj.11.11.9285482. View

12.

Wu Y, Gao Z, Chen B, Koval O, Singh M, Guan X . Calmodulin kinase II is required for fight or flight sinoatrial node physiology. Proc Natl Acad Sci U S A. 2009; 106(14):5972-7. PMC: 2667018. DOI: 10.1073/pnas.0806422106. View

13.

Vila-Petroff M, Salas M, Said M, Valverde C, Sapia L, Portiansky E . CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia-reperfusion injury. Cardiovasc Res. 2007; 73(4):689-98. DOI: 10.1016/j.cardiores.2006.12.003. View

14.

van Oort R, McCauley M, Dixit S, Pereira L, Yang Y, Respress J . Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation. 2010; 122(25):2669-79. PMC: 3075419. DOI: 10.1161/CIRCULATIONAHA.110.982298. View

15.

Mann D, McMurray J, Packer M, Swedberg K, Borer J, Colucci W . Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004; 109(13):1594-602. DOI: 10.1161/01.CIR.0000124490.27666.B2. View

16.

Zhang T, Zhang Y, Cui M, Jin L, Wang Y, Lv F . CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat Med. 2016; 22(2):175-82. DOI: 10.1038/nm.4017. View

17.

Burgos J, Yeves A, Barrena J, Portiansky E, Vila-Petroff M, Ennis I . Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training. J Mol Cell Cardiol. 2017; 112:16-26. DOI: 10.1016/j.yjmcc.2017.08.014. View

18.

Kung G, Konstantinidis K, Kitsis R . Programmed necrosis, not apoptosis, in the heart. Circ Res. 2011; 108(8):1017-36. DOI: 10.1161/CIRCRESAHA.110.225730. View

19.

Pocock S, Ariti C, McMurray J, Maggioni A, Kober L, Squire I . Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J. 2012; 34(19):1404-13. DOI: 10.1093/eurheartj/ehs337. View

20.

Singh M, Kapoun A, Higgins L, Kutschke W, Thurman J, Zhang R . Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart. J Clin Invest. 2009; 119(4):986-96. PMC: 2662543. DOI: 10.1172/JCI35814. View