GW29-e0751 Sestrin2 is involved in endoplasmic reticulum stress induced atrial fibrillation

Background Mitral regurgitation (MR) is a major contributor for heart failure (HF) and atrial fibrillation. Despite the advancement of MR surgeries, an effective medical therapy to mitigate MR progression is lacking. Sodium glucose cotransporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality but the mechanism is unclear. We hypothesized that dapagliflozin (DAPA), a sodium glucose cotransporter 2 inhibitor, can improve cardiac hemodynamics in MR‐induced HF. Methods and Results Using a novel, mini‐invasive technique, we established a MR model in rats, in which MR induced left heart dilatation and functional decline. Half of the rats were randomized to be administered with DAPA at 10 mg/kg per day for 6 weeks. After evaluation of electrocardiography and echocardiography, hemodynamic studies were performed, followed by postmortem tissue analyses. Results showed that DAPA partially rescued MR‐induced impairment including partial restoration of left ventricular ejection fraction and end‐systolic pressure volume relationship. Despite no significant changes in electrocardiography at rest, rats treated with DAPA exhibited lower inducibility and decreased duration of pacing‐induced atrial fibrillation. DAPA also significantly attenuated cardiac fibrosis, cardiac expression of apoptosis, and endoplasmic reticulum stress‐associated proteins. Conclusions DAPA was able to suppress cardiac fibrosis and endoplasmic reticulum stress and improve hemodynamics in an MR‐induced HF rat model. The demonstrated DAPA effect on the heart and its association with key molecular contributors in eliciting its cardio‐protective function, provides a plausible point of DAPA as a potential strategy for MR‐induced HF.

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IP3R1/GRP75/VDAC1 complex mediated endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling

EP Europace ◽

10.1093/europace/euab116.562 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

T Liu ◽

M Yuan ◽

M Gong ◽

J He ◽

Z Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Atrial Fibrillation ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Conditional Knockout ◽

Proximity Ligation Assay ◽

Atrial Remodeling ◽

Mitochondrial Oxidative Stress

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): National Natural Science Foundation of China Background Mitochondrial oxidative stress is an important mechanism of atrial remodeling and atrial fibrillation (AF) in the setting of diabetes. Currently, endoplasmic reticulum (ER) stress is regarded as the key link from homeostasis to dysfunction, and is a central feature of metabolic diseases such as type 2 diabetes. However, the molecular mechanisms underlying these processes have not been fully elucidated. Objective To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. Methods Mouse atrial cardiomyocytes (HL-1 cells) , type 2 diabetic rats and GRP75 conditional knockout mice were used as models systems. These findings were correlated with biomarker findings in human diabetic patients with confirmed atrial fibrillation. Results In the diabetic rat atria, significant ER stress was observed. Treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) demonstrated many known ER stress and calmodulin proteins, including Heat shock protein family A (Hsp70) member (Hspa) 5 (GRP78) and Hspa9 (GRP75) and in situ proximity ligation assay (PLA) indicated that TM led to increased protein expression of the IP3R1 (inositol 1,4,5-trisphosphate receptors 1)/GRP75 (glucose-regulated protein 75)/VDAC1 (voltage-dependent anion channel 1) complex in HL-1 cells. Silencing of GRP75 using siRNA in HL-1 cells and GRP75 conditional knockout in our mouse model led to impaired calcium transport from the ER to mitochondria, and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuates atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. Conclusions The IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress plays an important role in diabetic atrial remodeling. Abstract Figure

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Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress

Frontiers in Pharmacology ◽

10.3389/fphar.2021.690371 ◽

2021 ◽

Vol 12 ◽

Author(s):

Heng-Jing Hu ◽

Xiu-Heng Wang ◽

Yao Liu ◽

Tian-Qing Zhang ◽

Zheng-Rong Chen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Endoplasmic Reticulum ◽

Hydrogen Sulfide ◽

Endoplasmic Reticulum Stress ◽

Warburg Effect ◽

Dichloroacetic Acid ◽

Atrial Fibrosis ◽

Fibrosis Progression ◽

Sd Rats ◽

The Warburg Effect

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-β-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

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