TY - JOUR
T1 - Cardiomyocyte and endothelial cells play distinct roles in the tumour necrosis factor (TNF)-dependent atrial responses and increased atrial fibrillation vulnerability induced by endurance exercise training in mice
AU - Lakin, Robert
AU - Polidovitch, Nazari
AU - Yang, Sibao
AU - Parikh, Mihir
AU - Liu, Xueyan
AU - Debi, Ryan
AU - Gao, Xiaodong
AU - Chen, Wenliang
AU - Guzman, Camilo
AU - Yakobov, Simona
AU - Izaddoustdar, Farzad
AU - Wauchop, Marianne
AU - Lei, Qian
AU - Xu, Weimin
AU - Nedospasov, Sergei A.
AU - Christoffels, Vincent M.
AU - Backx, Peter H.
N1 - Funding Information: Canadian Institutes of Health Research (CIHR) provided a Post-doctoral Fellowship to R.L. P.H.B. acknowledges project grants from the CIHR (MOP-119339, MOP 125950 and PJT-180391), a Canada Research Chair in Cardiovascular Biology from the CIHR, and a John Evans Leader Award for equipment from the Canadian Foundation for Innovation. V.M.C. received support from Fondation Leducq (14CVD01). Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Aims: Endurance exercise is associated with an increased risk of atrial fibrillation (AF). We previously established that adverse atrial remodelling and AF susceptibility induced by intense exercise in mice require the mechanosensitive and pro-inflammatory cytokine tumour necrosis factor (TNF). The cellular and mechanistic basis for these TNF-mediated effects is unknown. Methods and results: We studied the impact of Tnf excision, in either atrial cardiomyocytes or endothelial cells (using Cre-recombinase expression controlled by Nppa or Tie2 promoters, respectively), on the cardiac responses to six weeks of intense swim exercise training. TNF ablation, in either cell type, had no impact on the changes in heart rate, autonomic tone, or left ventricular structure and function induced by exercise training. Tnf excision in atrial cardiomyocytes did, however, prevent atrial hypertrophy, fibrosis, and macrophage infiltration as well as conduction slowing and increased AF susceptibility arising from exercise training. In contrast, endothelial-specific excision only reduced the training-induced atrial hypertrophy. Consistent with these cell-specific effects of Tnf excision, inducing TNF loss from atrial cardiomyocytes prevented activation of p38MAPKinase, a strain-dependent downstream mediator of TNF signalling, without affecting the atrial stretch as assessed by atrial pressures induced by exercise. Despite TNF's established role in innate immune responses and inflammation, neither acute nor chronic exercise training caused measurable NLRP3 inflammasome activation. Conclusions: Our findings demonstrate that adverse atrial remodelling and AF vulnerability induced by intense exercise require TNF in atrial cardiomyocytes whereas the impact of endothelial-derived TNF is limited to hypertrophy modulation. The implications of the cell autonomous effects of TNF and crosstalk between cells in the atria are discussed.
AB - Aims: Endurance exercise is associated with an increased risk of atrial fibrillation (AF). We previously established that adverse atrial remodelling and AF susceptibility induced by intense exercise in mice require the mechanosensitive and pro-inflammatory cytokine tumour necrosis factor (TNF). The cellular and mechanistic basis for these TNF-mediated effects is unknown. Methods and results: We studied the impact of Tnf excision, in either atrial cardiomyocytes or endothelial cells (using Cre-recombinase expression controlled by Nppa or Tie2 promoters, respectively), on the cardiac responses to six weeks of intense swim exercise training. TNF ablation, in either cell type, had no impact on the changes in heart rate, autonomic tone, or left ventricular structure and function induced by exercise training. Tnf excision in atrial cardiomyocytes did, however, prevent atrial hypertrophy, fibrosis, and macrophage infiltration as well as conduction slowing and increased AF susceptibility arising from exercise training. In contrast, endothelial-specific excision only reduced the training-induced atrial hypertrophy. Consistent with these cell-specific effects of Tnf excision, inducing TNF loss from atrial cardiomyocytes prevented activation of p38MAPKinase, a strain-dependent downstream mediator of TNF signalling, without affecting the atrial stretch as assessed by atrial pressures induced by exercise. Despite TNF's established role in innate immune responses and inflammation, neither acute nor chronic exercise training caused measurable NLRP3 inflammasome activation. Conclusions: Our findings demonstrate that adverse atrial remodelling and AF vulnerability induced by intense exercise require TNF in atrial cardiomyocytes whereas the impact of endothelial-derived TNF is limited to hypertrophy modulation. The implications of the cell autonomous effects of TNF and crosstalk between cells in the atria are discussed.
KW - Atrial fibrillation
KW - Exercise
KW - Heart
KW - Inflammation
KW - Tumour necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=85176830642&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/cvr/cvad144
DO - https://doi.org/10.1093/cvr/cvad144
M3 - Article
C2 - 37713664
SN - 0008-6363
VL - 119
SP - 2607
EP - 2622
JO - Cardiovascular research
JF - Cardiovascular research
IS - 16
ER -