Atrial Fibrillation: Recent Advances in Understanding the Role of MicroRNAs in Atrial Remodeling with an Electrophysiological Overview

Cardiology ◽  
2015 ◽  
Vol 131 (1) ◽  
pp. 58-67 ◽  
Author(s):  
Pradeep Poudel ◽  
Yanmin Xu ◽  
Zhanqian Cui ◽  
Deepak Sharma ◽  
Bing Tian ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Molecular Diagnostic ◽  
Transcriptional Level ◽  
Atrial Remodeling ◽  
Structural Remodeling ◽  
Recent Advances ◽  
Novel Therapeutic

Atrial fibrillation (AF) is a highly prevalent condition associated with pronounced cardiovascular-related morbidity, mortality and socioeconomic burden. It accounts for more hospitalization days than does any other arrhythmia. This article reviews the basic electrophysiology of AF, electrical and structural remodeling in AF and recent advances in understanding the molecular mechanisms of AF in relation to specific microRNAs. This paper also reviews the potential role of microRNAs as novel therapeutic targets as well as biomarkers in the management of AF. AF shows characteristics typical of altered electrophysiology that promote ectopic activity and facilitate reentry, thereby contributing to the progression from short paroxysmal AF to a persistent, permanent form via atrial remodeling, even in the absence of progressive underlying heart disease. MicroRNAs have been suggested to influence the development of AF by regulating gene expression at the post-transcriptional level. Increasing evidence has identified various microRNA modifications and their impacts on AF initiation and maintenance through electrical and structural remodeling. The discovery of specific microRNAs as novel therapeutic targets and some experimental evidence implicating microRNAs as potential molecular diagnostic markers have had a significant impact on the diagnosis and management of AF and demand further research.

scholarly journals Cellular and mitochondrial mechanisms of atrial fibrillation

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Fleur E. Mason ◽  
Julius Ryan D. Pronto ◽  
Khaled Alhussini ◽  
Christoph Maack ◽  
Niels Voigt
Keyword(s):  
Atrial Fibrillation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Specific Treatment ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Mitochondrial Activity ◽  
Atp Production

AbstractThe molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

scholarly journals The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yanan Jiang ◽  
Xiuyun Shen ◽  
Moyondafoluwa Blessing Fasae ◽  
Fengnan Zhi ◽  
Lu Chai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Pathogenic Mechanism ◽  
Research Progress ◽  
Biological Processes ◽  
And Function ◽  
Novel Therapeutic

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

scholarly journals Atrial Fibrillation Progression Is Associated with Cell Senescence Burden as Determined by p53 and p16 Expression

2019 ◽  
Vol 9 (1) ◽  
pp. 36
Author(s):  
Laurence Jesel ◽  
Malak Abbas ◽  
Sin-Hee Park ◽  
Kensuke Matsushita ◽  
Michel Kindo ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Heart Surgery ◽  
Open Heart Surgery ◽  
Right Atrial ◽  
Atrial Remodeling ◽  
Inflammatory Proteins ◽  
Underlying Mechanisms ◽  
The Right ◽  
New Evidence

Background: Whilst the link between aging and thrombogenicity in atrial fibrillation (AF) is well established, the cellular underlying mechanisms are unknown. In AF, the role of senescence in tissue remodeling and prothrombotic state remains unclear. Aims: We investigated the link between AF and senescence by comparing the expression of senescence markers (p53 and p16), with prothrombotic and inflammatory proteins in right atrial appendages from patients in AF and sinus rhythm (SR). Methods: The right atrial appendages of 147 patients undergoing open-heart surgery were harvested. Twenty-one non-valvular AF patients, including paroxysmal (PAF) or permanent AF (PmAF), were matched with 21 SR patients according to CHA2DS2-VASc score and treatment. Protein expression was assessed by tissue lysates Western blot analysis. Results: The expression of p53, p16, and tissue factor (TF) was significantly increased in AF compared to SR (0.91 ± 0.31 vs. 0.58 ± 0.31, p = 0.001; 0.76 ± 0.32 vs. 0.35 ± 0.18, p = 0.0001; 0.88 ± 0.32 vs. 0.68 ± 0.29, p = 0.045, respectively). Expression of endothelial NO synthase (eNOS) was lower in AF (0.25 ± 0.15 vs. 0.35 ± 0.12, p = 0.023). There was a stepwise increase of p53, p16, TF, matrix metalloproteinase-9, and an eNOS progressive decrease between SR, PAF, and PmAF. AF was the only predictive factor of p53 and p16 elevation in multivariate analysis. Conclusions: The study brought new evidence indicating that AF progression is strongly related to human atrial senescence burden and points at a link between senescence, thrombogenicity, endothelial dysfunction and atrial remodeling.

scholarly journals The Role of MicroRNAs in Hepatoblastoma Tumors

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 409 ◽  
Author(s):  
Ion Cristóbal ◽  
Marta Sanz-Álvarez ◽  
Melani Luque ◽  
Cristina Caramés ◽  
Federico Rojo ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Strategies ◽  
Substantial Contribution ◽  
Hepatic Malignancy ◽  
Recent Advances

Hepatoblastoma is the most common hepatic malignancy during childhood. However, little is still known about the molecular mechanisms that govern the development of this disease. This review is focused on the recent advances regarding the study of microRNAs in hepatoblastoma and their substantial contribution to improv our knowledge of the pathogenesis of this disease. We show here that miRNAs represent valuable tools to identify signaling pathways involved in hepatoblastoma progression as well as useful biomarkers and novel molecular targets to develop alternative therapeutic strategies in this disease.

Molecular Interactions of α-Synuclein, Mitochondria, and Cellular Degradation Pathways in Parkinson's Disease

2020 ◽  
pp. 212-234
Author(s):  
Mansi Verma ◽  
Sujata Basu ◽  
Manisha Singh ◽  
Rachana R. ◽  
Simrat Kaur ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Interactions ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Degradation Pathways ◽  
Functional Changes ◽  
The World ◽  
Novel Therapeutic

Parkinson's disease (PD) has been reported to be the most common neurodegenerative diseases all over the world. Several proteins are associated and responsible for causing PD. One such protein is α-synuclein. This chapter discusses the role of α-synuclein in PD. Various genetic and epigenetic factors, which cause structural and functional changes for α-synuclein, have been described. Several molecular mechanisms, which are involved in regulating mitochondrial and lysosomal related pathways and are linked to α-synuclein, have been discussed in detail. The knowledge gathered is further discussed in terms of using α-synuclein as a diagnostic marker for PD and as a novel therapeutic target for the same.

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