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1.
Int J Mol Sci ; 23(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36430389

RESUMO

Arrhythmogenic Cardiomyopathy (ACM) is a familial heart disease, characterized by contractile dysfunction, ventricular arrhythmias (VAs), and the risk of sudden cardiac death. Currently, implantable cardioverter defibrillators and antiarrhythmics are the mainstays in ACM therapeutics. Angiotensin receptor blockers (ARBs) have been highlighted in the treatment of heart diseases, including ACM. Yet, recent research has additionally implicated ARBs in the genesis of VAs and myocardial lipolysis via the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. The latter is of particular interest, as fibrofatty infiltration is a pathological hallmark in ACM. Here, we tested two ARBs, Valsartan and Telmisartan, and the PPAR agonist, Rosiglitazone, in an animal model of ACM, homozygous Desmoglein-2 mutant mice (Dsg2mut/mut). Cardiac function, premature ventricular contractions (PVCs), fibrofatty scars, PPARα/γ protein levels, and PPAR-mediated mRNA transcripts were assessed. Of note, not a single mouse treated with Rosiglitazone made it to the study endpoint (i.e., 100% mortality: n = 5/5). Telmisartan-treated Dsg2mut/mut mice displayed the preservation of contractile function (percent ejection fraction [%EF]; 74.8 ± 6.8%EF) compared to Vehicle- (42.5 ± 5.6%EF) and Valsartan-treated (63.1 ± 4.4%EF) mice. However, Telmisartan-treated Dsg2mut/mut mice showed increased cardiac wall motion abnormalities, augmented %PVCs, electrocardiographic repolarization/depolarization abnormalities, larger fibrotic lesions, and increased expression of PPARy-regulated gene transcripts compared to their Dsg2mut/mut counterparts. Alternatively, Valsartan-treated Dsg2mut/mut mice harbored fewer myocardial scars, reduced %PVC, and increased Wnt-mediated transcripts. Considering our findings, caution should be taken by physicians when prescribing medications that may increase PPARy signaling in patients with ACM.


Assuntos
Cardiomiopatias , Cardiopatias , Animais , Camundongos , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cicatriz , PPAR alfa , Rosiglitazona , Telmisartan/farmacologia
2.
Circulation ; 140(18): 1491-1505, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31533459

RESUMO

BACKGROUND: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. METHODS: To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. RESULTS: Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of JUP2157del2 in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 [Dsg2mut/mut]) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of Dsg2mut/mut mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. CONCLUSIONS: Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.


Assuntos
Arritmias Cardíacas/metabolismo , Cardiomiopatias/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Animais , Arritmias Cardíacas/patologia , Cardiomiopatias/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos Transgênicos , Ratos Wistar , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
3.
JCI Insight ; 2(15)2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-28768908

RESUMO

Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-ß ligands, with increased TGF-ß signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-ß, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-ß ligand expression that culminates in both autocrine and paracrine overdrive of TGF-ß signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.

4.
Cardiovasc Res ; 113(1): 102-111, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28069705

RESUMO

AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. CONCLUSIONS: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adulto , Antígenos CD/metabolismo , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Displasia Arritmogênica Ventricular Direita/metabolismo , Sistemas CRISPR-Cas , Caderinas/metabolismo , Diferenciação Celular , Análise Mutacional de DNA , Eletrocardiografia , Exoma , Feminino , Edição de Genes/métodos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Imageamento por Ressonância Magnética , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Análise Multinível , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Países Baixos , Fenótipo , Sódio/metabolismo , Transfecção , Estados Unidos , Adulto Jovem
5.
JCI Insight ; 1(5)2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27170944

RESUMO

Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3ß inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice. GSK3ß inhibition improved left ventricle function and survival in sedentary and exercised Dsg2mut/mut mice compared with Veh-treated Dsg2mut/mut mice and normalized intercalated disc (ID) protein distribution in both mutant mice. GSK3ß showed diffuse cytoplasmic localization in control myocytes but ID redistribution in ACM mice. Identical GSK3ß redistribution is present in ACM patient myocardium but not in normal hearts or other cardiomyopathies. SB2 reduced total GSK3ß protein levels but not phosphorylated Ser 9-GSK3ß in ACM mice. Constitutively active GSK3ß worsens ACM in mutant mice, while GSK3ß shRNA silencing in ACM cardiomyocytes prevents abnormal ID protein distribution. These results highlight a central role for GSKß in the complex phenotype of ACM and provide further evidence that pharmacologic GSKß inhibition improves cardiomyopathies due to desmosome mutations.

6.
J Cardiovasc Transl Res ; 9(1): 87-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26733327

RESUMO

Prior reports have identified associations between SCN10A and cardiac disorders, such as atrial fibrillation and Brugada syndrome. We evaluated SCN10A in 151 probands with ARVD/C. In this cohort, 10 putatively pathogenic SCN10A variants were identified, including a novel frameshift insertion. Despite a known role for the encoded protein in peripheral nerve function, the proband with the frameshift variant had no discernible neurological abnormalities. Arrhythmic phenotypes were not different between those with a rare variant in SCN10A and those without. The prevalence of rare variants in SCN10A was similar among ARVD/C probands with and without a desmosome mutation and similar among healthy Caucasian controls. These results indicate the absence of a primary role for SCN10A mutations in ARVD/C.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Adulto , Displasia Arritmogênica Ventricular Direita/diagnóstico , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Adulto Jovem
7.
Nat Commun ; 5: 3416, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24595103

RESUMO

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas/metabolismo , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Humanos , Imuno-Histoquímica , Camundongos , Dados de Sequência Molecular , Mutação , Proteínas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Am J Med Genet A ; 161A(2): 371-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23307527

RESUMO

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial form of cardiomyopathy typically caused by mutations in genes that encode an element of the cardiac desmosome. Branchio-oculo-facial syndrome (BOFS) is a craniofacial disorder caused by TFAP2A mutations. In a family segregating ARVD/C, some members also had features of BOFS. Genetic testing for ARVD/C identified a mutation in PKP2, encoding plakophilin-2, a component of the cardiac desmosome. Evaluation of dysmorphology by chromosome microarray (CMA) identified a 4.4 Mb deletion at chromosome 6p24 that included both TFAP2A and DSP, encoding desmoplakin, an additional component of the cardiac desmosome implicated in ARVD/C. A family member with both the 6p24 deletion and PKP2 mutation had more severe cardiac dysfunction. These findings suggest that this contiguous gene deletion contributes to both ARVD/C and BOFS, and that DSP haploinsufficiency may contribute to cardiomyopathy. This family provides a clinical example that underscores the need for careful evaluation in clinical scenarios where genetic heterogeneity is known to exist. Finally, it suggests that individuals with unexplained cardiomyopathy and dysmorphic facial features may benefit from CMA analysis.


Assuntos
Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Síndrome Brânquio-Otorrenal/diagnóstico por imagem , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Síndrome Brânquio-Otorrenal/genética , Síndrome Brânquio-Otorrenal/fisiopatologia , Deleção Cromossômica , Cromossomos Humanos Par 6 , Feminino , Estudos de Associação Genética , Humanos , Técnicas de Diagnóstico Molecular , Linhagem , Fenótipo , Volume Sistólico , Ultrassonografia
9.
J Cardiovasc Transl Res ; 3(6): 663-73, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20857253

RESUMO

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited form of cardiomyopathy with low penetrance and variable expressivity. Dominant mutations and rare polymorphisms in desmosome genes are frequently identified. We reasoned that individuals with earlier onset disease would have more frequent desmosome gene mutations and rare polymorphisms. Three groups were compared: Young with symptoms attributable to ARVD/C or a diagnosis of ARVD/C at age of 21 years or earlier, Middle with first symptoms or diagnosis age of 22-49 years, and Late with first symptoms or diagnosis at age of 50 or more years. deoxyribonucleic acid (DNA) sequence analysis was performed on five cardiac desmosome genes, and the presence of mutations and rare missense polymorphisms was compared among the three groups. In the entire Young cohort, 20 (67%) had one or more cardiac desmosome gene mutations. The prevalence of cardiac desmosome gene mutations was similar in the Middle (48%) and Late (53%) cohorts (P = 0.23). Similar numbers of individuals in each cohort had more than one desmosome gene mutation, although the numbers are too small for statistical comparisons. The prevalence of certain rare missense DNA variants was not different among the cohorts (P = 0.71), yet these rare missense alleles were more prevalent in the overall study cohort of 112 ARVD/C participants compared to 100 race-matched controls (P = 0.027). The presence of these variants did not associate with the age of onset of ARVD/C or ventricular tachycardia. These findings highlight the complex interplay of environmental and genetic factors contributing to this condition.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Desmossomos/genética , Mutação , Polimorfismo Genético , Adolescente , Adulto , Idade de Início , Idoso , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Baltimore , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Sistema de Registros , Medição de Risco , Fatores de Risco , Adulto Jovem
10.
Circ Cardiovasc Genet ; 2(5): 428-35, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20031617

RESUMO

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C. METHODS AND RESULTS: In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation. CONCLUSIONS: Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Desmossomos/genética , Mutação , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Desmocolinas/química , Desmocolinas/genética , Desmogleína 2/química , Desmogleína 2/genética , Desmoplaquinas/química , Desmoplaquinas/genética , Desmossomos/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , América do Norte , Linhagem , Placofilinas/química , Placofilinas/genética , Alinhamento de Sequência , Adulto Jovem , gama Catenina
11.
Am J Hum Genet ; 79(1): 136-42, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16773573

RESUMO

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a disorder characterized by fibrofatty replacement of cardiac myocytes that typically manifests in the right ventricle. It is inherited as an autosomal dominant disease with reduced penetrance, although autosomal recessive forms of the disease also occur. We identified four probands with ARVD/C caused by mutations in DSG2, which encodes desmoglein-2, a component of the cardiac desmosome. No association between mutations in this gene and human disease has been reported elsewhere. One of these probands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2. We report that mutations in DSG2 contribute to the development of ARVD/C.


Assuntos
Arritmias Cardíacas/genética , Cardiomegalia/genética , Desmogleína 2/genética , Ventrículos do Coração/patologia , Mutação , Sequência de Aminoácidos , Animais , Sequência de Bases , Primers do DNA , Desmogleína 2/química , Humanos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
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