Fibrosis in Right Atrium Tissue of Patient with Atrial Fibrillation: Role of Rac1and Its Inhibitor-statins
|School||Chongqing Medical University|
|Keywords||atrial fibrillation Atrial Fibrosis Activated Rac1 Statins Collagen|
BackgroundAtrial fibrillation (AF) is the most common supraventriculararrhythmia associated with a highly mortality and morbidity, which isbecoming a unsolved problem in cardiovascular field. The pathologicalmechanism of AF is unclear. Atrial fibrosis occurs as a common endpointin variety of heart diseases, including senescence, hypertension[3,4],heart failure[5,6], mitral valvular disease[7,8]and atrial fibrillation[9-11]. Theformation of atrial fibrosis resulted in atrial systolic dysfunction, aberrantconduction increase and atrial enlargement, which supplied a substrateof AF[6-9]. Several researches showed that atrial structural remodelingaccompanied with the formation of atrial fibrosis. Meanwhile, atrialfibrillation had also aggravated the formation of atrial fibrosis. Thus,atrial fibrosis and atrial fibrillation interacted as both cause and effect,became a vicious circle. At present, the specific mechanism of atrialfibrosis remained unclear. Meanwhile, Evolving evidence has suggestedthat the activation of rennin-angiotensin system (RAS) is one of the most vital mechanisms in formation of atrial fibrosis[9,17]. Moreover, themitogen-activated protein kinases (MAPKs), Janus kinase/signaltransducers and activators of transcription (JAK/STAT) pathway,apoptosis signal-regulating kinase1/nuclear factor kappa-B(ASK1/NF-κB), transcription growth factor-β1(TGF-β1), plateletderived growth factor (PDGF), activatedRac1inflammation and so on,which were participated in formation of atrial fibrosis[9,15-18,37]. Rac1, asmall GTPase binding protein, was involved with the pathogenesis ofatrial fibrillation in human and animal experimental[9,16,17]. But theunderlying mechanism of atrial fibrosis reduced by activated Rac1remains unclear. Thus, to study the role of activated Rac1and to studythe intervention effection of statins on the formation mechanism ofatrial fibrosis, it further provided vital evidence for preventing orreversing atrial fibrillation.ObjectivesTo investigate whether the small GTPase-binding protein Rac1isinvolved in atrial fibrosis formation, and further to investigate the effect of itsinhibitor-statins in patients with atrial fibrillation.MethodsIn102patients with atrial fibrillation (including50patients with statintreatment and52patients non-treated) and55patients with sinus rhythm(SR), Collagen type I and collagen type III are measured by quantitative western blot, the collagen volume fraction (CVF) is measured by Masson’strichrome staining, and activated Rac1is measured by GST-p21-activatedkinase pull-down assay.Results1. In right atrial appendage tissues of AF and sinus rhythm (SR) patients,the expression of activated Rac1Rac1(2.78(1.22) vs.1.47(0.62), p<0.0001),the collagen volume fraction (CVF)(43.26%(10.25%) vs.16.04%(4.04%),p<0.0001), collagen type I (1.21(0.71) vs.0.53(0.32), p<0.0001) andcollagen type III (0.85(0.32) vs.0.61(0.49), p=0.0086) were higher inpatients with AF compared with those in SR group, and there weresignificant statistical differences (all p<0.01).2. In right atrial appendage tissues of AF patients, the activated Rac1(3.34(1.26) vs.1.99(0.74), p<0.0001), CVF (48.42%(8.55%) vs.38.10%(9.29%), p=0.0004), collagen type I (1.66(0.64) vs.0.76(0.36), p<0.0001)and collagen type III (1.04(0.30) vs.0.65(0.19), p<0.0001) were higher inpatients not treated with statins than those treated with statins, and there weresignificant statistical differences (all p<0.001).3. Through the correlation analysis, the expression level of activatedRac1was correlated with CVF, collagen type I, and collagen type III notonly in patients with AF or SR but also within the subgroups of AF patientswith or without statin treatment (all p<0.05). Conclusions1. In right atrial appendage tissues of AF and SR patients, the seriousdegree of atrial fibrosis accompany with the a large number of expression ofactivated Rac1, thus, it reemphasizes that the activated Rac1plays animportant role in the formation of atrial fibrosis.2. Through the statins intervention, it was found that the expressionlevels of activated Rac1were reduced accompanying with the degree of atrialfibrosis alleviated, compared with the patients which those not treated withstatins.