Identification of Biomarkers Related to Atrial Fibrillation With Mitral Regurgitation

Yu, Jiajian; Zhou, Yu; Liu, Liwen; Zhang, Kunyi; Gao, Lijuan; He, Xupeng; Dong, Haojian

doi:10.1016/j.amjms.2020.10.007

Cited by 4 publications

(2 citation statements)

References 24 publications

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“…61 Recent studies suggest that STC-2 might also be a good biomarker for AF associated with mitral regurgitation and myocardial infarction. 61,62 Meanwhile, BNIP3 was reportedly increased in heart failure with reduced EF patients. 63 Knockdown of BNIP3 in a murine model of heart failure with reduced EF can improve glycolysis and mitochondrial metabolism and restore the sarcoplasmic reticulum-mitochondrial Ca 2+ homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

Wang

Song

Yuan

et al. 2023

Circulation Research

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Background: Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of FKBP5 (encoding FKBP5 [FK506 binding protein 5]). However, the function of FKBP5 in the heart remains unknown. Here, we elucidate the consequences of cardiomyocyte-restricted loss of FKBP5 on cardiac function and AF development and study the underlying mechanisms. Methods: Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding Fkbp5 flox/flox mice with Myh6 MerCreMer/+ mice. Cardiac function and AF inducibility were assessed by echocardiography and programmed intracardiac stimulation. Histology, optical mapping, cellular electrophysiology, and biochemistry were employed to elucidate the proarrhythmic mechanisms due to loss of cardiomyocyte FKBP5. Results: FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent chronic AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca 2+ waves, and increased protein levels and activity of the NCX1 (Na + /Ca 2+ -exchanger 1), mimicking the cellular phenotype of chronic AF patients. FKBP5-deficiency enhanced transcription of Slc8a1 (encoding NCX1) via transcription factor hypoxia-inducible factor 1α. In vitro studies revealed that FKBP5 negatively modulated the protein levels of hypoxia-inducible factor 1α by competitively interacting with heat-shock protein 90. Injections of the heat-shock protein 90 inhibitor 17-AAG normalized protein levels of hypoxia-inducible factor 1α and NCX1 and reduced AF susceptibility in cardiomyocyte-specific knockdown mice. Furthermore, the atrial cardiomyocyte-selective knockdown of FKBP5 was sufficient to enhance AF arrhythmogenesis. Conclusions: This is the first study to demonstrate a role for the FKBP5-deficiency in atrial arrhythmogenesis and to establish FKBP5 as a negative regulator of hypoxia-inducible factor 1α in cardiomyocytes. Our results identify a potential molecular mechanism for the proarrhythmic NCX1 upregulation in chronic AF patients.

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Section: Discussionmentioning

confidence: 99%

Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

Wang

Song

Yuan

et al. 2023

Circulation Research

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“…Yu et al (2021) also investigated the relationship between ECM organization and AF progression, besides metabolic dysregulation and the vitamin D response. They observed that hub genes, such as APP, CDH2, SPP1, and STC2, are differentially expressed in this condition [ 40 ]. Many other studies also point to structural remodeling in AF pathophysiology due to interactome perturbations.…”

Section: Structural Remodelingmentioning

confidence: 99%

Reviewing Atrial Fibrillation Pathophysiology from a Network Medicine Perspective: The Relevance of Structural Remodeling, Inflammation, and the Immune System

Martins

Almeida

Souza

et al. 2023

Life

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Atrial fibrillation (AF) is the most common type of sustained arrhythmia. The numerous gaps concerning the knowledge of its mechanism make improving clinical management difficult. As omics technologies allow more comprehensive insight into biology and disease at a molecular level, bioinformatics encompasses valuable tools for studying systems biology, as well as combining and modeling multi-omics data and networks. Network medicine is a subarea of network biology where disease traits are considered perturbations within the interactome. With this approach, potential disease drivers can be revealed, and the effect of drugs, novel or repurposed, used alone or in combination, may be studied. Thus, this work aims to review AF pathology from a network medicine perspective, helping researchers to comprehend the disease more deeply. Essential concepts involved in network medicine are highlighted, and specific research applying network medicine to study AF is discussed. Additionally, data integration through literature mining and bioinformatics tools, with network building, is exemplified. Together, all of the data show the substantial role of structural remodeling, the immune system, and inflammation in this disease etiology. Despite this, there are still gaps to be filled about AF.

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Omitted Funding Source

2021

The American Journal of the Medical Sciences

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Identification of Biomarkers Related to Atrial Fibrillation With Mitral Regurgitation

Cited by 4 publications

References 24 publications

Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

Reviewing Atrial Fibrillation Pathophysiology from a Network Medicine Perspective: The Relevance of Structural Remodeling, Inflammation, and the Immune System

Omitted Funding Source

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