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Background and Purpose: Atrial metabolic remodeling plays a critical role in the pathogenesis of atrial fibrillation (AF). Sirtuin3 (Sirt3) plays an important role in energy homeostasis. However, the effect of Sirt3 agonist Honokiol (HL) on AF is unclear. Therefore, the aim of this study is to determine the effect of HL on atrial metabolic remodeling in AF and to explore possible mechanisms. Experimental Approach: irt3 and glycogen deposition in left atria of AF patients were examined. Twenty-one rabbits were divided into sham, P (pacing for 3 weeks), P + H treatment (honokiol injected with pacing for 3 weeks). The HL-1 cells were subjected to rapid pacing at 5 Hz for 24 h, in the presence or absence of HL and overexpression or siRNA of Sirt3 by transfection. Metabolic factors, circulating metabolites, atrial electrophysiology, ATP level, and glycogens deposition were detected. Acetylated protein and activity of its enzymes were detected. Key Results: Sirt3 was significantly down-regulated in AF patients and rabbit/HL-1cell model, resulting in the abnormal expression of its downstream metabolic key factors, which were significantly restored by HL. Meanwhile, AF induced an increase of the acetylation level in long-chain acyl-CoA dehydrogenase (LCAD), AceCS2 and GDH, following decreasing of activity of it enzymes, resulting in abnormal alterations of metabolites and reducing of ATP, which was inhibited by HL. The Sirt3 could regulate acetylated modification of key metabolic enzymes, and the increase of Sirt3 rescued AF induced atrial metabolic remodeling. Conclusion and Implications: HL inhibited atrial metabolic remodeling in AF via the Sirt3 pathway. The present study may provide a novel therapeutical strategy for AF.
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Methods: Overall, 18 rabbits were randomly divided into control, pacing (600 beats/min), and pacing+sac/val groups. The rabbits in the pacing+sac/val cohort received oral sac/val (10 mg/kg twice daily) across the 21-day investigation period. After three weeks, the atrial effective refractory period (AERP) and AF induction rate were compared. HL-1 cultures were exposed to fast pacing (24 h) with and without LBQ657 (active sacubitril form)/valsartan. Western blots were used for detecting Cav1.2 and CaMKII expression within atrial muscles of the rabbits and HL-1 cultures of AF model. Results: In comparison to the sham cohort, the AF induction rate was markedly increased together with AERP reduction within pacing cohort. Such changes were markedly rescued through sac/val treatment in pacing+sac/val cohort. The proteomic expression profiles of CaMKII and Cav1.2 showed that the CaMKII expression was markedly upregulated, while Cav1.2 expression was downregulated in the pacing cohort. Importantly, these effects were absent in pacing+sac/val cohort. Conclusion: Results of this study show that sac/val treatment regulates the expression of CaMKII/Cav1.2 and could alter this pathway in atrial rapid electrical stimulation models. Therefore, this investigation could contribute to a novel strategy in AF therapeutics in clinical settings.
RESUMO
Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen â and â ¢, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen â and â ¢, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.
