NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias
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NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias. / Scott, Larry; Fender, Anke C.; Saljic, Arnela; Li, Luge; Chen, Xiaohui; Wang, Xiaolei; Linz, Dominik; Lang, Jilu; Hohl, Mathias; Twomey, Darragh; Pham, Thuy T.; Diaz-Lankenau, Rodrigo; Chelu, Mihail G.; Kamler, Markus; Entman, Mark L.; Taffet, George E.; Sanders, Prashanthan; Dobrev, Dobromir; Li, Na.
In: Cardiovascular Research, Vol. 117, No. 7, 2021, p. 1746-1759.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias
AU - Scott, Larry
AU - Fender, Anke C.
AU - Saljic, Arnela
AU - Li, Luge
AU - Chen, Xiaohui
AU - Wang, Xiaolei
AU - Linz, Dominik
AU - Lang, Jilu
AU - Hohl, Mathias
AU - Twomey, Darragh
AU - Pham, Thuy T.
AU - Diaz-Lankenau, Rodrigo
AU - Chelu, Mihail G.
AU - Kamler, Markus
AU - Entman, Mark L.
AU - Taffet, George E.
AU - Sanders, Prashanthan
AU - Dobrev, Dobromir
AU - Li, Na
PY - 2021
Y1 - 2021
N2 - Aims Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF.Methods and results Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of and obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3(-/-)) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3(-/-) mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3(-/-)) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice.Conclusion These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.
AB - Aims Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF.Methods and results Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of and obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3(-/-)) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3(-/-) mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3(-/-)) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice.Conclusion These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.
KW - Atrial fibrillation
KW - Obesity
KW - NLRP3 inflammasome
KW - RISK-FACTOR
KW - FIBRILLATION
KW - INITIATION
KW - PROTEIN
KW - PHOSPHORYLATION
KW - PERPETUATION
KW - PROGRESSION
KW - COHORT
KW - HEART
KW - MODEL
U2 - 10.1093/cvr/cvab024
DO - 10.1093/cvr/cvab024
M3 - Journal article
C2 - 33523143
VL - 117
SP - 1746
EP - 1759
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 7
ER -
ID: 274612528