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

Abstract

BackgroundDerailment 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 ResultsTachypacing 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.ConclusionsThese 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.

Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation

“…Garcia et al first reported impaired cardiac autophagy characterized by reduced LC3 processing (i.e., a reduced protein expression of LC3BⅡ) with an accumulation of lipofuscin deposit — a potential trigger of AF — in the atrial myocardium in patients with post-operative AF [15]. A pair of studies have shown that in chronic AF patients, the cardiac autophagy characterized by an increased protein expression of LC3BⅡ is induced in the atrial myocardium in association with AMPK or endoplasmic reticulum (ER) stress [13, 14]. Our present findings demonstrated that the atrial gene expression of LC3 was upregulated in the patients with chronic AF.…”

“…Accordingly, autophagy may regulate the fatty acid metabolism in cardiomyocytes. Alterations of the autophagy in the atrial muscles of patients with persistent AF [13, 14] or post-operative AF have been reported [15]. Although it is still controversial whether the induction of autophagy has a cardioprotective or detrimental effect in AF, it is possible that autophagy is involved in metabolic remodeling in the atrium in chronic AF patients.…”

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

“…There are strong indications that defective interactions between the ER and mitochondria may contribute to AF pathogenesis. In experimental AF models and AF patients, ER stress is present, which induces autophagy and, thereby, cardiac remodeling [74]. Importantly, overexpression of the ER chaperone GRP78 or prevention of ER stress by treatment with the chemical chaperone 4-PBA protected against cardiac remodeling and AF in experimental cardiomyocytes, Drosophila melanogaster, and a dog model for AF [74].…”

“…In experimental AF models and AF patients, ER stress is present, which induces autophagy and, thereby, cardiac remodeling [74]. Importantly, overexpression of the ER chaperone GRP78 or prevention of ER stress by treatment with the chemical chaperone 4-PBA protected against cardiac remodeling and AF in experimental cardiomyocytes, Drosophila melanogaster, and a dog model for AF [74]. Moreover, ER stress may activate mitogen-activated protein kinases (MAPKs), which initiate the mitochondrial apoptotic pathway [75].…”

Alteration of calcium signalling in cardiomyocyte induced by simulated microgravity and hypergravity

“…Although HL‐1 cells derive from atrial myocytes, they maintain the ability to contract and retain differentiated cardiac morphological, biochemical and electrophysiological properties . HL‐1 cells have thus proven useful as a model for studying contracting cardiomyocytes, because of their organized structure and ability to contract in culture; HL‐1 cells have been used in many studies of myocardial remodelling . Here, we report that calcium signalling plays a pivotal role in regulating gravity alteration‐induced cardiac remodelling through the Ca 2+ /CaMKII/HDAC4 signalling pathway.…”