TY - JOUR
T1 - Prevention of Atrial Fibrillation
T2 - Putting Proteostasis Derailment Back on Track
AU - Kishore, Preetam
AU - Collinet, Amelie C. T.
AU - Brundel, Bianca J. J. M.
N1 - Funding Information: This research was funded by the Dutch Heart Foundation (2020-2020B003 to B.J.J.M.B.), NWA-ORC project CIRCULAR NWO (NWA.1389.20.157) and the Atrial Fibrillation Innovation Platform foundation (AFIPonline.org, accessed on 26 April 2023). Publisher Copyright: © 2023 by the authors.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - Despite the many attempts to treat atrial fibrillation (AF), the most common cardiac tachyarrhythmia in the Western world, the treatment efficacy of AF is still suboptimal. A plausible reason for the suboptimal efficacy is that the current treatments are not directed at the underlying molecular mechanisms that drive AF. Recent discoveries revealed that the derailment of specific molecular proteostasis pathways drive electrical conduction disorders, contractile dysfunction and AF. The degree of this so-called ‘electropathology’ corresponds to the response to anti-AF treatment. Hence, to develop effective therapies to prevent AF, understanding the molecular mechanisms is of key importance. In this review, we highlight the key modulators of proteostasis derailment and describe the mechanisms that explain how they affect electrical and contractile function in atrial cardiomyocytes and AF. The key modulators of proteostasis derailment include (1) exhaustion of cardioprotective heat shock proteins (HSPs), (2) excessive endoplasmic reticulum (ER) stress and downstream autophagic protein degradation, (3) histone deacetylase 6 (HDAC6)-induced microtubule disruption, (4) activation of DNA damage-PARP1 activation and NAD+ axis and (5) mitochondrial dysfunction. Furthermore, we discuss druggable targets within these pathways that are involved in the prevention of proteostasis derailment, as well as the targets that aid in the recovery from AF. Finally, we will elaborate on the most favorable druggable targets for (future) testing in patients with AF, as well as drugs with potential benefits for AF recovery.
AB - Despite the many attempts to treat atrial fibrillation (AF), the most common cardiac tachyarrhythmia in the Western world, the treatment efficacy of AF is still suboptimal. A plausible reason for the suboptimal efficacy is that the current treatments are not directed at the underlying molecular mechanisms that drive AF. Recent discoveries revealed that the derailment of specific molecular proteostasis pathways drive electrical conduction disorders, contractile dysfunction and AF. The degree of this so-called ‘electropathology’ corresponds to the response to anti-AF treatment. Hence, to develop effective therapies to prevent AF, understanding the molecular mechanisms is of key importance. In this review, we highlight the key modulators of proteostasis derailment and describe the mechanisms that explain how they affect electrical and contractile function in atrial cardiomyocytes and AF. The key modulators of proteostasis derailment include (1) exhaustion of cardioprotective heat shock proteins (HSPs), (2) excessive endoplasmic reticulum (ER) stress and downstream autophagic protein degradation, (3) histone deacetylase 6 (HDAC6)-induced microtubule disruption, (4) activation of DNA damage-PARP1 activation and NAD+ axis and (5) mitochondrial dysfunction. Furthermore, we discuss druggable targets within these pathways that are involved in the prevention of proteostasis derailment, as well as the targets that aid in the recovery from AF. Finally, we will elaborate on the most favorable druggable targets for (future) testing in patients with AF, as well as drugs with potential benefits for AF recovery.
KW - DNA damage
KW - atrial fibrillation
KW - autophagy
KW - electropathology
KW - endoplasmic reticulum stress
KW - heat shock proteins
KW - histone deacetylases
KW - microtubules
KW - mitochondria
KW - proteostasis
KW - recovery
UR - http://www.scopus.com/inward/record.url?scp=85165046206&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/jcm12134352
DO - https://doi.org/10.3390/jcm12134352
M3 - Review article
C2 - 37445387
SN - 0009-9147
VL - 12
JO - Clinical Chemistry
JF - Clinical Chemistry
IS - 13
M1 - 4352
ER -