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Guo YH, Yang YQ. Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions. BIOLOGY 2022; 11:489. [PMID: 35453689 PMCID: PMC9029470 DOI: 10.3390/biology11040489] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 06/14/2023]
Abstract
Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have been causally linked to AF, of which the majority encode ion channels, cardiac structural proteins, transcription factors and gap junction channels. In the heart, gap junctions comprised of connexins (Cxs) form intercellular pathways responsible for electrical coupling and rapid coordinated action potential propagation between adjacent cardiomyocytes. Among the 21 isoforms of connexins already identified in the mammal genomes, 5 isoforms (Cx37, Cx40, Cx43, Cx45 and Cx46) are expressed in human heart. Abnormal electrical coupling between cardiomyocytes caused by structural remodeling of gap junction channels (alterations in connexin distribution and protein levels) has been associated with enhanced susceptibility to AF and recent studies have revealed multiple causative mutations or polymorphisms in 4 isoforms of connexins predisposing to AF. In this review, an overview of the genetics of AF is made, with a focus on the roles of mutant myocardial connexins and gap junctions in the pathogenesis of AF, to underscore the hypothesis that cardiac connexins are a major molecular target in the management of AF.
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Affiliation(s)
- Yu-Han Guo
- Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China;
| | - Yi-Qing Yang
- Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China;
- Cardiovascular Research Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China
- Center Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China
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Fu F, Pietropaolo M, Cui L, Pandit S, Li W, Tarnavski O, Shetty SS, Liu J, Lussier JM, Murakami Y, Grewal PK, Deyneko G, Turner GM, Taggart AKP, Waters MG, Coughlin S, Adachi Y. Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models. PLoS One 2022; 17:e0256512. [PMID: 34995278 PMCID: PMC8741011 DOI: 10.1371/journal.pone.0256512] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 12/23/2021] [Indexed: 12/19/2022] Open
Abstract
The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.
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Affiliation(s)
- Fumin Fu
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Michael Pietropaolo
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Lei Cui
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Shilpa Pandit
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Weiyan Li
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Oleg Tarnavski
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Suraj S. Shetty
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Jing Liu
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Jennifer M. Lussier
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Yutaka Murakami
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Prabhjit K. Grewal
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Galina Deyneko
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Gordon M. Turner
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Andrew K. P. Taggart
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - M. Gerard Waters
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Shaun Coughlin
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
| | - Yuichiro Adachi
- Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts, United State of America
- * E-mail:
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The Role of Proteostasis in the Regulation of Cardiac Intercellular Communication. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1233:279-302. [DOI: 10.1007/978-3-030-38266-7_12] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Abstract
Background Atrial fibrillation (AF) is a common arrhythmia seen in clinical practice. Occasionally, no common risk factors are present in patients with this arrhythmia. This suggests the potential underlying role of genetic factors associated with predisposition to developing AF. Methods and Results We conducted a comprehensive review of the literature through large online libraries, including PubMed. Many different potassium and sodium channel mutations have been discussed in their relation to AF. There have also been non–ion channel mutations that have been linked to AF. Genome‐wide association studies have helped in identifying potential links between single‐nucleotide polymorphisms and AF. Ancestry studies have also highlighted a role of genetics in AF. Blacks with a higher percentage of European ancestry are at higher risk of developing AF. The emerging field of ablatogenomics involves the use of genetic profiles in their relation to recurrence of AF after catheter ablation. Conclusions The evidence for the underlying role of genetics in AF continues to expand. Ultimately, the role of genetics in risk stratification of AF and its recurrence is of significant interest. No established risk scores that are useful in clinical practice are present to date.
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Affiliation(s)
- Julien Feghaly
- 1 Department of Internal Medicine St Louis University Hospital St Louis MO
| | - Patrick Zakka
- 2 Department of Internal Medicine Emory University Hospital Atlanta GA
| | - Barry London
- 3 Department of Cardiovascular Medicine University of Iowa Carver College of Medicine Iowa City IA
| | - Calum A MacRae
- 4 Department of Cardiovascular Medicine Brigham and Women's Hospital Boston MA
| | - Marwan M Refaat
- 5 Department of Cardiovascular Medicine American University of Beirut Medical Center Beirut Lebanon
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Lozano-Velasco E, Garcia-Padilla C, Aránega AE, Franco D. Genetics of Atrial Fibrilation: In Search of Novel Therapeutic Targets. Cardiovasc Hematol Disord Drug Targets 2019; 19:183-194. [PMID: 30727926 DOI: 10.2174/1871529x19666190206150349] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 01/16/2019] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic disease in humans, ranging from 2% in the general population and rising up to 10-12% in 80+ years. Genetic analyses of AF familiar cases have identified a series of point mutations in distinct ion channels, supporting a causative link. However, these genetic defects only explain a minority of AF patients. Genomewide association studies identified single nucleotide polymorphisms (SNPs), close to PITX2 on 4q25 chromosome, that are highly associated to AF. Subsequent GWAS studies have identified several new loci, involving additional transcription and growth factors. Furthermore, these risk 4q25 SNPs serve as surrogate biomarkers to identify AF recurrence in distinct surgical and pharmacological interventions. Experimental studies have demonstrated an intricate signalling pathway supporting a key role of the homeobox transcription factor PITX2 as a transcriptional regulator. Furthermore, cardiovascular risk factors such as hyperthyroidism, hypertension and redox homeostasis have been identified to modulate PITX2 driven gene regulatory networks. We provide herein a state-of-the-art review of the genetic bases of atrial fibrillation, our current understanding of the genetic regulatory networks involved in AF and its plausible usage for searching novel therapeutic targets.
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Affiliation(s)
- Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Carlos Garcia-Padilla
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Amelia E Aránega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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Noureldin M, Chen H, Bai D. Functional Characterization of Novel Atrial Fibrillation-Linked GJA5 (Cx40) Mutants. Int J Mol Sci 2018; 19:E977. [PMID: 29587382 PMCID: PMC5979441 DOI: 10.3390/ijms19040977] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/16/2018] [Accepted: 03/21/2018] [Indexed: 12/18/2022] Open
Abstract
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Recently, four novel heterozygous Cx40 mutations-K107R, L223M, Q236H, and I257L-were identified in 4 of 310 unrelated AF patients and a followup genetic analysis of the mutant carriers' families showed that the mutants were present in all the affected members. To study possible alterations associated with these Cx40 mutants, including their cellular localization and gap junction (GJ) function, we expressed GFP-tagged and untagged mutants in connexin-deficient model cells. All four Cx40 mutants showed clustered localization at cell-cell junctions similar to that observed of wildtype Cx40. However, cell pairs expressing Cx40 Q236H, but not the other individual mutants, displayed a significantly lower GJ coupling conductance (Gj) than wildtype Cx40. Similarly, co-expression of Cx40 Q236H with Cx43 resulted in a significantly lower Gj. Transjunctional voltage-dependent gating (Vj gating) properties were also altered in the GJs formed by Q236H. Reduced GJ function and altered Vj gating may play a role in promoting the Q236H carriers to AF.
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Affiliation(s)
- Mahmoud Noureldin
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1 Canada.
| | - Honghong Chen
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1 Canada.
| | - Donglin Bai
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1 Canada.
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Kanthan A, Fahmy P, Rao R, Pouliopoulos J, Alexander IE, Thomas SP, Kizana E. Human Connexin40 Mutations Slow Conduction and Increase Propensity for Atrial Fibrillation. Heart Lung Circ 2018; 27:114-121. [PMID: 28457700 DOI: 10.1016/j.hlc.2017.02.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 12/20/2016] [Accepted: 02/06/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Patch clamping studies using non-cardiomyocytes revealed that the human connexin40 mutations P88S, G38D, and A96S are associated with reduced gap junction conductances compared to wild type connexin40 (wtCx40). Their effects within myocytes however are unclear. We aimed to characterise P88S, G38D, and A96S after expression in rat hearts and primary cardiomyocyte cultures. METHODS Adult Sprague-Dawley rat atria were transduced with a lentivector containing a transgene encoding wtCx40, P88S, G38D, A96S, or eGFP (n=6 per transgene). Electrophysiology studies (EPS) were performed just prior to and 7 days after surgery. Left atria were assessed for connexin expression, mRNA levels, inflammation and fibrosis. Primary cardiomyocyte cultures were also transduced with the abovementioned vectors (n=6 per transgene) and monolayer conduction velocities (CV) and protein expression were assessed at 96hours. RESULTS At day 7 EPS, P wave and induced atrial fibrillation (AF) durations were significantly longer in the mutant groups when compared to wtCx40 controls (p<0.05). There were no significant differences in inflammation, fibrosis, or heart to body weight ratios. Monolayer CV's were reduced in the A96S group compared to the wtCx40 group. While similar to wtCx40 controls, P88S velocities were reduced compared to eGFP controls. G38D monolayers possessed spontaneous fibrillatory activity and could not be paced. Immunofluorescence revealed that P88S and G38D reduced native connexin43 myocyte coupling while A96S appeared to co-localise with connexin43 in gap junctions. Connexin43 mRNA levels were similar between groups. CONCLUSIONS The A96S, G38D, and P88S Cx40 mutations slow conduction and increased the propensity for inducible AF.
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Affiliation(s)
- Ajita Kanthan
- Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Westmead Institute for Medical Research, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia.
| | - Peter Fahmy
- Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Westmead Institute for Medical Research, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Renuka Rao
- Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Westmead Institute for Medical Research, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Jim Pouliopoulos
- Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Westmead Institute for Medical Research, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Ian E Alexander
- The University of Sydney, Sydney, NSW, Australia; Childrens Medical Research Institute, Sydney, NSW, Australia
| | - Stuart P Thomas
- Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Westmead Institute for Medical Research, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Eddy Kizana
- Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia; Westmead Institute for Medical Research, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
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8
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Abstract
Atrial fibrillation (AF) is a common clinical arrhythmia that appears to be highly heritable, despite representing a complex interplay of several disease processes that generally do not manifest until later in life. In this manuscript, we will review the genetic basis of this complex trait established through studies of familial AF, linkage and candidate gene studies of common AF, genome wide association studies (GWAS) of common AF, and transcriptomic studies of AF. Since AF is associated with a five-fold increase in the risk of stroke, we also review the intersection of common genetic factors associated with both of these conditions. Similarly, we highlight the intersection of common genetic markers associated with some risk factors for AF, such as hypertension and obesity, and AF. Lastly, we describe a paradigm where genetic factors predispose to the risk of AF, but which may require additional stress and trigger factors in older age to allow for the clinical manifestation of AF.
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Affiliation(s)
| | - Mina K Chung
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., J2-2, Cleveland, OH, 44195, USA.
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9
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Ye WG, Yue B, Aoyama H, Kim NK, Cameron JA, Chen H, Bai D. Junctional delay, frequency, and direction-dependent uncoupling of human heterotypic Cx45/Cx43 gap junction channels. J Mol Cell Cardiol 2017; 111:17-26. [PMID: 28760564 DOI: 10.1016/j.yjmcc.2017.07.117] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/10/2017] [Accepted: 07/27/2017] [Indexed: 01/15/2023]
Abstract
Gap junction (GJ) channels form low resistance passages between cardiomyocytes and play a role in the rapid propagation of action potentials in the heart. A GJ channel is formed by two properly docked hemichannels and each hemichannel is a hexamer of connexins. Connexin40 (Cx40) and Cx43 are the dominant connexins in atrial myocytes, while Cx45 is mostly expressed in the sinoatrial (SA) and atrioventricular (AV) nodes which directly connect nodal cells with atrial myocytes, possibly via heterotypic Cx40/Cx45 and/or Cx43/Cx45 GJs. However, the functional status and channel properties of human heterotypic Cx40/Cx45 or Cx43/Cx45 GJs have not been studied. Here we investigated human Cx40/Cx45 and Cx43/Cx45 heterotypic GJs by recombinant expression in GJ deficient cells. Unlike the finding on rodent connexins, cell pairs expressing human Cx40 in one and Cx45 in the other failed to form morphological and functional GJs. Modifications in human Cx40 with designed variants (D55N or P193Q, but not P193K) are sufficient to establish morphological and functional heterotypic GJs with Cx45. In contrast, heterotypic human Cx43/Cx45 GJs are functional similar to that described for rodent Cx43/Cx45 GJs. Detailed kinetic characterizations of human heterotypic Cx43/Cx45 GJs revealed a rapid asymmetric Vj-gating and a much slower recovery, which could reduce the GJ conductance in a junctional delay, action potential frequency, and direction dependent manner. Dynamic uncoupling in Cx45-containing GJs might contribute to a slower action potential propagation in the AV node.
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Affiliation(s)
- Willy G Ye
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Benny Yue
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Hiroshi Aoyama
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Nicholas K Kim
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - John A Cameron
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Honghong Chen
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Donglin Bai
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
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10
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Hood AR, Ai X, Pogwizd SM. Regulation of cardiac gap junctions by protein phosphatases. J Mol Cell Cardiol 2017; 107:52-57. [PMID: 28478048 DOI: 10.1016/j.yjmcc.2017.05.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 04/13/2017] [Accepted: 05/02/2017] [Indexed: 01/16/2023]
Abstract
Sufficient connexin-mediated intercellular coupling is critical to maintain gap junctional communication for proper cardiac function. Alterations in connexin phosphorylation state, particularly dephosphorylation of connexin 43 (Cx43), may impact cell coupling and conduction in disease states. Cx43 dephosphorylation may be carried out by protein phosphatase activity. Here, we present an overview of the key phosphatases known to interact with Cx43 or modulators of Cx43, as well as some possible therapeutic targets to regulate phosphatase activity in the heart.
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Affiliation(s)
- Ashleigh R Hood
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Xun Ai
- Department of Biophysics and Physiology, Rush University, Chicago, IL, United States
| | - Steven M Pogwizd
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, United States; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
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11
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Franco D, Lozano-Velasco E, Aranega A. Gene regulatory networks in atrial fibrillation. World J Med Genet 2016; 6:1-16. [DOI: 10.5496/wjmg.v6.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 12/15/2015] [Accepted: 02/17/2016] [Indexed: 02/06/2023] Open
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic syndrome in humans. With an estimate incidence of 1%-2% in the general population, AF raises up to almost 10%-12% in 80+ years. Thus, AF represents nowadays a highly prevalent medical problem generating a large economic burden. At the electrophysiological level, distinct mechanisms have been elucidated. Yet, despite its prevalence, the genetic and molecular culprits of this pandemic cardiac electrophysiological abnormality have remained largely obscure. Molecular genetics of AF familiar cases have demonstrated that single nucleotide mutations in distinct genes encoding for ion channels underlie the onset of AF, albeit such alterations only explain a minor subset of patients with AF. In recent years, analyses by means of genome-wide association studies have unraveled a more complex picture of the etiology of AF, pointing out to distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Furthermore a new layer of regulatory mechanisms have emerged, i.e., post-transcriptional regulation mediated by non-coding RNA, which have been demonstrated to exert pivotal roles in cardiac electrophysiology. In this manuscript, we aim to provide a comprehensive review of the genetic regulatory networks that if impaired exert electrophysiological abnormalities that contribute to the onset, and subsequently, on self-perpetuation of AF.
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12
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Jassim A, Aoyama H, Ye WG, Chen H, Bai D. Engineered Cx40 variants increased docking and function of heterotypic Cx40/Cx43 gap junction channels. J Mol Cell Cardiol 2016; 90:11-20. [PMID: 26625713 DOI: 10.1016/j.yjmcc.2015.11.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 10/30/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023]
Abstract
Gap junction (GJ) channels provide low resistance passages for rapid action potential propagation in the heart. Both connexin40 (Cx40) and Cx43 are abundantly expressed in and frequently co-localized between atrial myocytes, possibly forming heterotypic GJ channels. However, conflicting results have been obtained on the functional status of heterotypic Cx40/Cx43 GJs. Here we provide experimental evidence that the docking and formation of heterotypic Cx40/Cx43 GJs can be substantially increased by designed Cx40 variants on the extracellular domains (E1 and E2). Specifically, Cx40 D55N and P193Q, substantially increased the probability to form GJ plaque-like structures at the cell-cell interfaces with Cx43 in model cells. More importantly the coupling conductance (Gj) of D55N/Cx43 and P193Q/Cx43 GJ channels are significantly increased from the Gj of Cx40/Cx43 in N2A cells. Our homology models indicate the electrostatic interactions and surface structures at the docking interface are key factors preventing Cx40 from docking to Cx43. Improving heterotypic Gj of these atrial connexins might be potentially useful in improving the coupling and synchronization of atrial myocardium.
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Affiliation(s)
- Arjewan Jassim
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Hiroshi Aoyama
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Willy G Ye
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Honghong Chen
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Donglin Bai
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
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13
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Christophersen IE, Ellinor PT. Genetics of atrial fibrillation: from families to genomes. J Hum Genet 2015; 61:61-70. [DOI: 10.1038/jhg.2015.44] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 03/27/2015] [Accepted: 04/07/2015] [Indexed: 12/19/2022]
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Wernhart S, Halle M. Atrial fibrillation and long-term sports practice: epidemiology and mechanisms. Clin Res Cardiol 2014; 104:369-79. [DOI: 10.1007/s00392-014-0805-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/16/2014] [Indexed: 12/19/2022]
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15
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Kelly JJ, Simek J, Laird DW. Mechanisms linking connexin mutations to human diseases. Cell Tissue Res 2014; 360:701-21. [DOI: 10.1007/s00441-014-2024-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 09/26/2014] [Indexed: 11/30/2022]
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16
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Molica F, Meens MJP, Morel S, Kwak BR. Mutations in cardiovascular connexin genes. Biol Cell 2014; 106:269-93. [PMID: 24966059 DOI: 10.1111/boc.201400038] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 06/20/2014] [Indexed: 12/25/2022]
Abstract
Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighbouring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphoedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease.
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Affiliation(s)
- Filippo Molica
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Bai D. Atrial fibrillation-linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms. FEBS Lett 2014; 588:1238-43. [PMID: 24656738 DOI: 10.1016/j.febslet.2014.02.064] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 02/05/2014] [Accepted: 02/06/2014] [Indexed: 01/08/2023]
Abstract
The gap junctions (GJs) formed by Cx40 and Cx43 provide a low resistance passage allowing for rapid propagation of action potentials. Sporadic somatic mutations in GJA5 (encoding Cx40) have been identified in lone atrial fibrillation (AF) patients. More recently germline autosomal dominantly inherited mutations in GJA5 have been found in early onset lone AF patients in several families over generations. Characterizations of these AF-linked Cx40 mutants in model cells and in patient tissues revealed that some of the mutants reduced GJ channel function due to an impaired trafficking or channel formation. While others showed a gain-of-function in hemichannels. These functional alterations in GJs or hemichannel may play an important role in the pathogenesis of AF in the mutant carriers.
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Affiliation(s)
- Donglin Bai
- Department of Physiology and Pharmacology, Western University, London, Ontario N6A 5C1, Canada.
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18
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Sun Y, Hills MD, Ye WG, Tong X, Bai D. Atrial fibrillation-linked germline GJA5/connexin40 mutants showed an increased hemichannel function. PLoS One 2014; 9:e95125. [PMID: 24733048 PMCID: PMC3986259 DOI: 10.1371/journal.pone.0095125] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 03/24/2014] [Indexed: 01/08/2023] Open
Abstract
Mutations in GJA5 encoding the gap junction protein connexin40 (Cx40) have been linked to lone atrial fibrillation. Some of these mutants result in impaired gap junction function due to either abnormal connexin localization or impaired gap junction channels, which may play a role in promoting atrial fibrillation. However, the effects of the atrial fibrillation-linked Cx40 mutants on hemichannel function have not been studied. Here we investigated two atrial fibrillation-linked germline Cx40 mutants, V85I and L221I. These two mutants formed putative gap junction plaques at cell-cell interfaces, with similar gap junction coupling conductance as that of wild-type Cx40. Connexin deficient HeLa cells expressing either one of these two mutants displayed prominent propidium iodide-uptake distinct from cells expressing wild-type Cx40 or other atrial fibrillation-linked Cx40 mutants, I75F, L229M, and Q49X. Propidium iodide-uptake was sensitive to [Ca2+]o and the hemichannel blockers, carbenoxolone, flufenamic acid and mefloquine, but was not affected by the pannexin 1 channel blocking agent, probenecid, indicating that uptake is most likely mediated via connexin hemichannels. A gain-of-hemichannel function in these two atrial fibrillation-linked Cx40 mutants may provide a novel mechanism underlying the etiology of atrial fibrillation.
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Affiliation(s)
- Yiguo Sun
- Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada
| | - Matthew D. Hills
- Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada
| | - Willy G. Ye
- Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada
| | - Xiaoling Tong
- Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada
| | - Donglin Bai
- Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada
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