The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology. / Mehdizadeh, Mozhdeh; Naud, Patrice; Abu-Taha, Issam H.; Hiram, Roddy; Xiong, Feng; Xiao, Jiening; Saljic, Arnela; Kamler, Markus; Vuong-Robillard, Nhung; Thorin, Eric; Ferbeyre, Gerardo; Tardif, Jean Claude; Sirois, Martin G.; Tanguay, Jean Francois; Dobrev, Dobromir; Nattel, Stanley.
In: Cardiovascular Research, Vol. 120, No. 5, 2024, p. 506-518.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology
AU - Mehdizadeh, Mozhdeh
AU - Naud, Patrice
AU - Abu-Taha, Issam H.
AU - Hiram, Roddy
AU - Xiong, Feng
AU - Xiao, Jiening
AU - Saljic, Arnela
AU - Kamler, Markus
AU - Vuong-Robillard, Nhung
AU - Thorin, Eric
AU - Ferbeyre, Gerardo
AU - Tardif, Jean Claude
AU - Sirois, Martin G.
AU - Tanguay, Jean Francois
AU - Dobrev, Dobromir
AU - Nattel, Stanley
N1 - Publisher Copyright: © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2024
Y1 - 2024
N2 - AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
AB - AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
KW - AF susceptibility
KW - Cellular senescence
KW - Fibrosis
KW - Myocardial infarction
KW - Senolytic drugs
U2 - 10.1093/cvr/cvae003
DO - 10.1093/cvr/cvae003
M3 - Journal article
C2 - 38181429
AN - SCOPUS:85189192272
VL - 120
SP - 506
EP - 518
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 5
ER -
ID: 391629902