TY - JOUR
T1 - Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice
AU - Mighiu, Alexandra S.
AU - Recalde, Alice
AU - Ziberna, Klemen
AU - Carnicer, Ricardo
AU - Tomek, Jakub
AU - Bub, Gil
AU - Brewer, Alison C.
AU - Verheule, Sander
AU - Shah, Ajay M.
AU - Simon, Jillian N.
AU - Casadei, Barbara
N1 - Funding Information:
This work was supported by the British Heart Foundation (RG/11/15/29375 to B.C., A.S.M., A.R., K.Z., and R.C.; CH/12/3/29609 to B.C. and J.N.S; RG/16/12/32451 to B.C., A.S.M., K.Z., and R.C.; and CH/1999001/11735 to A.M.S.) and, in part, by the Fondation Leducq Network of Excellence (08CVD01 to B.C. and A.R.). A.S.M was supported by a Radcliffe Department of Medicine (University of Oxford) Scholars Programme Studentship and the Clarendon Fund.
Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Aims: Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility. Methods and results: NOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype. Conclusion: Together, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.
AB - Aims: Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility. Methods and results: NOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype. Conclusion: Together, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.
KW - Arrhythmia (mechanisms)
KW - Atorvastatin
KW - Atrial fibrillation
KW - NADPH oxidases
KW - Oxidant stress
UR - http://www.scopus.com/inward/record.url?scp=85107046785&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvab019
DO - 10.1093/cvr/cvab019
M3 - Article
C2 - 33483749
AN - SCOPUS:85107046785
SN - 0008-6363
VL - 117
SP - 2354
EP - 2364
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 11
ER -