SR calcium handling dysfunction, stress-response signaling pathways, and atrial fibrillation

Background/Aims: Recent research has improved our understanding of the pulmonary vein and surrounding left atrial (LA-PV) junction and the left atrial appendage (LAA), which are considered the ‘trigger’ and ‘substrate’ in the development of atrial fibrillation (AF), respectively. Herein, with the aim of identifying the underlying potential genetic mechanisms, we compared differences in gene expression between LA-PV junction and LAA specimens via bioinformatic analysis. Methods: Microarray data of AF (GSE41177) were downloaded from the Gene Expression Omnibus database. In addition, linear models for microarray data limma powers differential expression analyses and weighted correlation network analysis (WGCNA) were applied. Results: From the differential expression analyses, 152 differentially expressed genes and hub genes, including LEP, FOS, EDN1, NMU, CALB2, TAC1, and PPBP, were identified. Our analysis revealed that the maps of extracellular matrix (ECM)-receptor interactions, PI3K-Akt and Wnt signaling pathways, and ventricular cardiac muscle tissue morphogenesis were significantly enriched. In addition, the WGCNA results showed high correlations between genes and related genetic clusters to external clinical characteristics. Maps of the ECM-receptor interactions, chemokine signaling pathways, and the cell cycle were significantly enriched in the genes of corresponding modules and closely associated with AF duration, left atrial diameter, and left ventricular ejection function, respectively. Similarly, mapping of the TNF signaling pathway indicated significant association with genetic traits of ischemic heart disease, hypertension, and diabetes comorbidity. Conclusions: The ECM-receptor interaction as a possible central node of comparison between LA-PV and LAA samples reflected the special functional roles of ‘triggers’ and ‘substrates’ and may be closely associated with AF duration. Furthermore, LEP, FOS, EDN1, NMU, CALB2, TAC1, and PPBP genes may be implicated in the occurrence and maintenance of AF through their interactions with each other.

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Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Signal Transduction Insights ◽

10.4137/sti.s39844 ◽

2016 ◽

Vol 5 ◽

pp. STI.S39844 ◽

Cited By ~ 2

Author(s):

Mohammad Ishaq ◽

Ven Natarajan

Keyword(s):

Stress Response ◽

Signaling Pathways ◽

Antiviral Agents ◽

Integrated Stress Response ◽

Dependent Protein Kinase ◽

Antiviral Responses ◽

Stress Markers ◽

Signaling Mechanisms ◽

Dependent Protein ◽

Vesicular Stomatitis

Supraphysiological concentrations (SPCs) of triiodo-L-thyronine (T3) have been used in the treatment of a number of nonviral diseases. However, the signaling mechanisms that regulate the function of T3 at these concentrations and their role in modulating cellular stress pathways and antiviral responses are unknown. Here, we have investigated the effects of SPCs of T3 on integrated stress response (ISR) signaling pathways and the replication of vesicular stomatitis virus (VSV). T3 amplified Poly IC-induced activation of RNA-dependent protein kinase, induced phosphorylation of eIF2α, stress granule (SG) formation, IRE1α phosphorylation, XBP1 splicing, and the expression of stress markers. T3 inhibited VSV replication by modulating SG formation and the expression of stress response markers. ISR activator guanabenz also inhibited VSV replication and amplified T3-induced anti-VSV response. To summarize, we have uncovered novel functions of T3 at SPCs as an activator of ISR signaling pathways and an inhibitor of VSV replication. This study offers a proof of principle of the concept that ISR activating agents like SPC of T3 and guanabenz can be potential antiviral agents.

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Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms21134655 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4655

Author(s):

Duo Feng ◽

DongZhu Xu ◽

Nobuyuki Murakoshi ◽

Kazuko Tajiri ◽

Rujie Qin ◽

...

Keyword(s):

Atrial Fibrillation ◽

Nicotinamide Adenine Dinucleotide ◽

Electrophysiological Study ◽

Redox Homeostasis ◽

Calcium Handling ◽

Nicotinamide Adenine ◽

Chow Diet ◽

Nicotinamide Phosphoribosyltransferase ◽

Nicotinamide Riboside ◽

Normal Chow

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF.

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