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Current Cardiology Reviews

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ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

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Review Article

ROCK (RhoA/Rho Kinase) Activation in Atrial Fibrillation: Molecular Pathways and Clinical Implications

Author(s): Riccardo Proietti*, Andrea S. Giordani and Calò A. Lorenzo

Volume 19, Issue 3, 2023

Published on: 13 December, 2022

Article ID: e171122210986 Pages: 6

DOI: 10.2174/1573403X19666221117092951

Price: $65

Abstract

Among the complex mechanisms of AF pathogenesis, intracellular calcium overload and oxidative stress play a major role, both triggered by inflammatory processes. The additional basic event taking place in AF is atrial fibrotic remodeling, again triggered by oxidative stress, which is determined by connexins rearrangement and differentiation of fibroblasts into active collagensecreting myofibroblasts. RhoA/ROCK system is the final pathway of a wide spectrum of molecular effectors such as Angiotensin II, platelet-derived growth factor, connective tissue growth factor and transforming growth factor β, that overall determine calcium dysregulation and pro-fibrotic remodeling. Both in experimental and clinical studies, RhoA/ROCK activation has been linked to superoxide ion production, fibrotic remodeling and connexins rearrangement, with important consequences for AF pathogenesis. ROCK pathway inhibition may therefore be a therapeutic or preventive target for special AF subgroups of patients.

Keywords: Rho kinase, atrial fibrillation, calcium overload, myocardial remodelling, atrial fibrosis, oxidative stress.

Graphical Abstract

[1]
Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013; 34(35): 2746-51.
[http://dx.doi.org/10.1093/eurheartj/eht280] [PMID: 23900699]
[2]
Proietti M, Laroche C, Nieuwlaat R, et al. Increased burden of comorbidities and risk of cardiovascular death in atrial fibrillation patients in Europe over ten years: A comparison between EORP-AF pilot and EHS-AF registries. Eur J Intern Med 2018; 55: 28-34.
[http://dx.doi.org/10.1016/j.ejim.2018.05.016] [PMID: 29778588]
[3]
Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-kinase in the cardiovascular system. Circ Res 2016; 118(2): 352-66.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306532] [PMID: 26838319]
[4]
Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertens 2001; 38: 1307-10.
[5]
Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E. Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial. J Neurol Sci 2005; 238(1-2): 31-9.
[http://dx.doi.org/10.1016/j.jns.2005.06.003] [PMID: 16005902]
[6]
Seccia TM, Rigato M, Ravarotto V, Calò LA. ROCK (RhoA/Rho Kinase) in cardiovascular–renal pathophysiology: A review of new advancements. J Clin Med 2020; 9(5): 1328.
[http://dx.doi.org/10.3390/jcm9051328] [PMID: 32370294]
[7]
Surma M, Wei L, Shi J. Rho kinase as a therapeutic target in cardiovascular disease. Future Cardiol 2011; 7(5): 657-71.
[http://dx.doi.org/10.2217/fca.11.51] [PMID: 21929346]
[8]
Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology: The effect of fasudil. J Cardiovasc Pharmacol 2013; 62(4): 341-54.
[http://dx.doi.org/10.1097/FJC.0b013e3182a3718f] [PMID: 23921309]
[9]
Dobrev D, Ravens U. Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res Cardiol 2003; 98(3): 137-48.
[http://dx.doi.org/10.1007/s00395-003-0409-8] [PMID: 12883831]
[10]
Wang X, Chen X, Dobrev D, Li N. The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation. Pflugers Arch 2021; 473(3): 389-405.
[http://dx.doi.org/10.1007/s00424-021-02515-4] [PMID: 33511453]
[11]
Williams GSB, Chikando AC, Tuan HTM, Sobie EA, Lederer WJ, Jafri MS. Dynamics of calcium sparks and calcium leak in the heart. Biophys J 2011; 101(6): 1287-96.
[http://dx.doi.org/10.1016/j.bpj.2011.07.021] [PMID: 21943409]
[12]
Dridi H, Kushnir A, Zalk R, Yuan Q, Melville Z, Marks AR. Intracellular calcium leak in heart failure and atrial fibrillation: A unifying mechanism and therapeutic target. Nat Rev Cardiol 2020; 17(11): 732-47.
[http://dx.doi.org/10.1038/s41569-020-0394-8] [PMID: 32555383]
[13]
Heijman J, Voigt N, Wehrens XHT, Dobrev D. Calcium dysregulation in atrial fibrillation: The role of CaMKII. Front Pharmacol 2014; 5: 30.
[http://dx.doi.org/10.3389/fphar.2014.00030] [PMID: 24624086]
[14]
Vest JA, Wehrens XHT, Reiken SR, et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 2005; 111(16): 2025-32.
[http://dx.doi.org/10.1161/01.CIR.0000162461.67140.4C] [PMID: 15851612]
[15]
Beavers DL, Wang W, Ather S, et al. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol 2013; 62(21): 2010-9.
[http://dx.doi.org/10.1016/j.jacc.2013.06.052] [PMID: 23973696]
[16]
Wehrens XHT. CaMKII regulation of the cardiac ryanodine receptor and SR calcium release. Heart Rhythm 2011; 8: 323-5.
[http://dx.doi.org/10.1016/j.hrthm.2010.09.079] [PMID: 20887810]
[17]
Karam BS, Chavez-Moreno A, Koh W, Akar JG, Akar FG. Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovasc Diabetol 2017; 16(1): 120.
[http://dx.doi.org/10.1186/s12933-017-0604-9] [PMID: 28962617]
[18]
Shan J, Xie W, Betzenhauser M, et al. Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia. Circ Res 2012; 111(6): 708-17.
[http://dx.doi.org/10.1161/CIRCRESAHA.112.273342] [PMID: 22828895]
[19]
Joseph LC, Barca E, Subramanyam P, et al. Inhibition of NAPDH Oxidase 2 (NOX2) prevents oxidative stress and mitochondrial abnormalities caused by saturated fat in cardiomyocytes. PLoS One 2016; 11(1): e0145750.
[http://dx.doi.org/10.1371/journal.pone.0145750] [PMID: 26756466]
[20]
Sohns C, Marrouche NF. Atrial fibrillation and cardiac fibrosis. Eur Heart J 2020; 41(10): 1123-31.
[http://dx.doi.org/10.1093/eurheartj/ehz786] [PMID: 31713590]
[21]
Nattel S. Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation. JACC Clin Electrophysiol 2017; 3(5): 425-35.
[http://dx.doi.org/10.1016/j.jacep.2017.03.002] [PMID: 29759598]
[22]
Harada M, Nattel S. Implications of inflammation and fibrosis in atrial fibrillation pathophysiology. Card Electrophysiol Clin 2021; 13(1): 25-35.
[http://dx.doi.org/10.1016/j.ccep.2020.11.002] [PMID: 33516403]
[23]
Lin X, Gemel J, Glass A, Zemlin CW, Beyer EC, Veenstra RD. Connexin40 and connexin43 determine gating properties of atrial gap junction channels. J Mol Cell Cardiol 2010; 48(1): 238-45.
[http://dx.doi.org/10.1016/j.yjmcc.2009.05.014] [PMID: 19486903]
[24]
Gemel J, Levy AE, Simon AR, et al. Connexin40 abnormalities and atrial fibrillation in the human heart. J Mol Cell Cardiol 2014; 76: 159-68.
[http://dx.doi.org/10.1016/j.yjmcc.2014.08.021] [PMID: 25200600]
[25]
Hauer RNW, Groenewegen WA, Firouzi M, Ramanna H, Jongsma HJ. Cx40 polymorphism in human atrial fibrillation. Adv Cardiol 2006; 42: 284-91.
[http://dx.doi.org/10.1159/000092579] [PMID: 16646598]
[26]
Ryu K, Li L, Khrestian CM, et al. Effects of sterile pericarditis on connexins 40 and 43 in the atria: Correlation with abnormal conduction and atrial arrhythmias. Am J Physiol Heart Circ Physiol 2007; 293(2): H1231-41.
[http://dx.doi.org/10.1152/ajpheart.00607.2006] [PMID: 17434983]
[27]
Gao HC, Zhao H, Zhang WQ, Li YQ, Ren LQ. The role of the Rho/Rock signaling pathway in the pathogenesis of acute ischemic myocardial fibrosis in rat models. Exp Ther Med 2013; 5(4): 1123-8.
[http://dx.doi.org/10.3892/etm.2013.935] [PMID: 23596480]
[28]
Wei L, Taffet GE, Khoury DS, et al. Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved. FASEB J 2004; 18(7): 857-9.
[http://dx.doi.org/10.1096/fj.03-0664fje] [PMID: 15033930]
[29]
Galvão I, Athayde RM, Perez DA, et al. ROCK inhibition drives resolution of acute inflammation by enhancing neutrophil apoptosis. Cells 2019; 8(9): 964.
[http://dx.doi.org/10.3390/cells8090964] [PMID: 31450835]
[30]
Zhou X, Dudley SC Jr. Evidence for inflammation as a driver of atrial fibrillation. Front Cardiovasc Med 2020; 7: 62.
[http://dx.doi.org/10.3389/fcvm.2020.00062] [PMID: 32411723]
[31]
Korantzopoulos P, Letsas KP, Tse G, Fragakis N, Goudis CA, Liu T. Inflammation and atrial fibrillation: A comprehensive review. J Arrhythm 2018; 34(4): 394-401.
[http://dx.doi.org/10.1002/joa3.12077] [PMID: 30167010]
[32]
Hu YF, Chen YJ, Lin YJ, Chen SA. Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 2015; 12: 230-43.
[33]
Yin Z, Zou Y, Wang D, et al. Regulation of the Tec family of non-receptor tyrosine kinases in cardiovascular disease. Cell Death Discov 2022; 8(1): 119.
[http://dx.doi.org/10.1038/s41420-022-00927-4] [PMID: 35296647]
[34]
Rolfe B, Worth N, World C, Campbell J, Campbell G. Rho and vascular disease. Atherosclerosis 2005; 183(1): 1-16.
[http://dx.doi.org/10.1016/j.atherosclerosis.2005.04.023] [PMID: 15982657]
[35]
Matsui T, Amano M, Yamamoto T, et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 1996; 15(9): 2208-16.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00574.x] [PMID: 8641286]
[36]
Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996; 392(2): 189-93.
[http://dx.doi.org/10.1016/0014-5793(96)00811-3] [PMID: 8772201]
[37]
Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005; 25(9): 1767-75.
[http://dx.doi.org/10.1161/01.ATV.0000176193.83629.c8] [PMID: 16002741]
[38]
Kimura K, Ito M, Amano M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-Kinase). Science 1996; 273: 245-8.
[39]
Tagawa M, Nakamura Y, Okura Y, et al. Successful treatment of acute fulminant eosinophilic myocarditis in a patient with ulcerative colitis using steroid therapy and percutaneous cardiopulmonary support. Intern Med 2019; 58(8): 1111-8.
[http://dx.doi.org/10.2169/internalmedicine.1528-18] [PMID: 30568130]
[40]
Schröder K. NADPH oxidase-derived reactive oxygen species: Dosis facit venenum. Exp Physiol 2019; 104(4): 447-52.
[http://dx.doi.org/10.1113/EP087125] [PMID: 30737851]
[41]
Higashi M, Shimokawa H, Hattori T, et al. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: Effect on endothelial NAD(P)H oxidase system. Circ Res 2003; 93(8): 767-75.
[http://dx.doi.org/10.1161/01.RES.0000096650.91688.28] [PMID: 14500337]
[42]
Jin L, Ying Z, Webb RC. Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am J Physiol Heart Circ Physiol 2004; 287(4): H1495-500.
[http://dx.doi.org/10.1152/ajpheart.01006.2003] [PMID: 15371261]
[43]
Juan-Zhang , Bian HJ, Li XX, et al.ERK-MAPK signaling opposes rho-kinase to reduce cardiomyocyte apoptosis in heart ischemic preconditioning. Mol Med 2010; 16(7-8): 307-15.
[http://dx.doi.org/10.2119/molmed.2009.00121] [PMID: 20383434]
[44]
Hu Q, Zheng G, Zweier JL, Deshpande S, Irani K, Ziegelstein RC. NADPH oxidase activation increases the sensitivity of intracellular Ca2+ stores to inositol 1,4,5-trisphosphate in human endothelial cells. J Biol Chem 2000; 275(21): 15749-57.
[http://dx.doi.org/10.1074/jbc.M000381200] [PMID: 10747906]
[45]
Radeff JM, Nagy Z, Stern PH. Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promoter activity in osteoblastic cells. J Bone Miner Res 2004; 19(11): 1882-91.
[http://dx.doi.org/10.1359/JBMR.040806] [PMID: 15476589]
[46]
Hiroki J, Shimokawa H, Higashi M, et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004; 37(2): 537-46.
[http://dx.doi.org/10.1016/j.yjmcc.2004.05.008] [PMID: 15276023]
[47]
Ma Z, Zhang J, Ji E, Cao G, Li G, Chu L. Rho kinase inhibition by fasudil exerts antioxidant effects in hypercholesterolemic rats. Clin Exp Pharmacol Physiol 2011; 38(10): 688-94.
[http://dx.doi.org/10.1111/j.1440-1681.2011.05561.x] [PMID: 21711379]
[48]
Adam O, Frost G, Custodis F, et al. Role of Rac1 GTPase activation in atrial fibrillation. J Am Coll Cardiol 2007; 50(4): 359-67.
[http://dx.doi.org/10.1016/j.jacc.2007.03.041] [PMID: 17659204]
[49]
Yao C, Veleva T, Scott L Jr, et al. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation 2018; 138(20): 2227-42.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035202] [PMID: 29802206]
[50]
Kikuchi Y, Yamada M, Imakiire T, et al. A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J Endocrinol 2007; 192(3): 595-603.
[http://dx.doi.org/10.1677/JOE-06-0045] [PMID: 17332527]
[51]
Kolavennu V, Zeng L, Peng H, Wang Y, Danesh FR. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes 2008; 57(3): 714-23.
[http://dx.doi.org/10.2337/db07-1241] [PMID: 18083785]
[52]
Jiang C, Huang H, Liu J, Wang Y, Lu Z, Xu Z. Fasudil, a Rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice. Int J Mol Sci 2012; 13(7): 8293-307.
[http://dx.doi.org/10.3390/ijms13078293] [PMID: 22942703]
[53]
Chen J, Li Q, Dong R, Gao H, Peng H, Wu Y. The effect of the Ras homolog gene family (Rho), member A/Rho associated coiled-coil forming protein kinase pathway in atrial fibrosis of type 2 diabetes in rats. Exp Ther Med 2014; 8(3): 836-40.
[http://dx.doi.org/10.3892/etm.2014.1843] [PMID: 25120610]
[54]
Guan S. Long-term administration of Fasudil improves cardiomyopathy in streptozotocin-induced diabetic rats. Food Chem Toxicol 2012; 50: 1874-82.
[http://dx.doi.org/10.1016/j.fct.2012.03.006] [PMID: 22429817]
[55]
Zhou H, Li Y, Wang M, et al. Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes. Acta Pharmacol Sin 2011; 32(8): 999-1008.
[http://dx.doi.org/10.1038/aps.2011.54] [PMID: 21743486]
[56]
Qiu H, Ji C, Liu W, et al. Chronic kidney disease increases atrial fibrillation inducibility: Involvement of inflammation, atrial fibrosis, and connexins. Front Physiol 2018; 9: 1726.
[http://dx.doi.org/10.3389/fphys.2018.01726] [PMID: 30564139]
[57]
Chen Y, Su F, Han J, Jiao P, Guo W. Expression of Rho kinase and its mechanism in the left atrial appendage in patients with atrial fibrillation. Heart Surg Forum 2018; 21(1): 044.
[http://dx.doi.org/10.1532/hsf.1851] [PMID: 29485964]
[58]
Calò LA, Ravarotto V, Bertoldi G, et al. Rho kinase activity, connexin 40, and atrial fibrillation: Mechanistic insights from end-stage renal disease on dialysis patients. J Clin Med 2020; 9(1): 165.
[http://dx.doi.org/10.3390/jcm9010165] [PMID: 31936157]
[59]
Calò LA, Vertolli U, Pagnin E, et al. Increased rho kinase activity in mononuclear cells of dialysis and stage 3–4 chronic kidney disease patients with left ventricular hypertrophy: Cardiovascular risk implications. Life Sci 2016; 148: 80-5.
[http://dx.doi.org/10.1016/j.lfs.2016.02.019] [PMID: 26872982]
[60]
Düzen IV, Yavuz F, Vuruskan E, et al. Investigation of leukocyte RHO/ROCK gene expressions in patients with non-valvular atrial fibrillation. Exp Ther Med 2019; 18(4): 2777-82.
[PMID: 31572525]

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