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J Am Heart Assoc. 2017 Oct 24;6(10). pii: e006458. doi: 10.1161/JAHA.117.006458.

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation.

Author information

1
Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands.
2
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
3
Department of Medicine, Montreal Heart Institute and Université de Montréal, the Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada.
4
Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University of Duisburg-Essen, Duisburg, Germany.
5
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
6
Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands.
7
Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands b.brundel@vumc.nl.

Abstract

BACKGROUND:

Derailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self-perpetuating nature of atrial fibrillation (AF), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF.

METHODS AND RESULTS:

Tachypacing of HL-1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC3B-II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca2+ amplitude. Autophagy is activated downstream of endoplasmic reticulum (ER) stress: blocking ER stress by the chemical chaperone 4-phenyl butyrate, overexpression of the ER chaperone-protein heat shock protein A5, or overexpression of a phosphorylation-blocked mutant of eukaryotic initiation factor 2α (eIF2α) prevents autophagy activation and Ca2+-transient loss in tachypaced HL-1 cardiomyocytes. Moreover, pharmacological inhibition of ER stress in tachypaced Drosophila confirms its role in derailing cardiomyocyte function. In vivo treatment with sodium salt of phenyl butyrate protected atrial-tachypaced dog cardiomyocytes from electrical remodeling (action potential duration shortening, L-type Ca2+-current reduction), cellular Ca2+-handling/contractile dysfunction, and ER stress and autophagy; it also attenuated AF progression. Finally, atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage.

CONCLUSIONS:

These results identify ER stress-associated autophagy as an important pathway in AF progression and demonstrate the potential therapeutic action of the ER-stress inhibitor 4-phenyl butyrate.

KEYWORDS:

4PBA; Drosophila; Endoplasmic Reticulum stress; HSPA5; atrial fibrillation; autophagy; drug research; molecular biology; structural biology; tachypacing

PMID:
29066441
PMCID:
PMC5721854
DOI:
10.1161/JAHA.117.006458
[Indexed for MEDLINE]
Free PMC Article

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