Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies

Fish, Maryam; Shaboodien, Gasnat; Kraus, Sarah; Sliwa, Karen; Seidman, Christine E.; Burke, Michael A.; Crotti, Lia; Schwartz, Peter J.; Mayosi, Bongani M.

doi:10.1038/srep22235

Cited by 34 publications

(26 citation statements)

References 33 publications

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“…In addition, multiple small genotyping studies identified a handful of heterozygous PLN mutations in individuals that were missense. 211, 212 Moreover, PLN mutations have been identified in individuals with HCM exclusively. These include a handful rare PLN promoter have been identified in multiple independent cohorts.…”

Section: Arrhythmias Caused By Heritable Defects In Calcium-handling mentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

433

331

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There has been significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electrical rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

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Section: Arrhythmias Caused By Heritable Defects In Calcium-handling mentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

433

331

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“…Calcium cycling is abnormal in young PLN R9C/+ mice before the onset of overt cardiac remodeling (denoted as pre-DCM). However, PLN R9C/+ mice subsequently develop DCM that consistently progresses to fulminant HF and premature death, (3) thus recapitulating the chronologic manifestations in human patients with this mutation (3–5). To delineate the longitudinal consequences of altered calcium homeostasis in cardiac remodeling, we studied the transcriptional changes in cardiomyocytes and nonmyocytes from pre-DCM through DCM to HF.…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

et al. 2016

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Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10−4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10−33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

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“…(5,6) PLN R9C mice display altered calcium handling prior to onset of phenotypic disease (preDCM) and ultimately develop progressive DCM with fulminant heart failure culminating in premature death. (4) This inexorable process mimics the disease course of individuals carrying this mutation (4,7,8) and recapitulates the natural history of DCM.…”

Section: Introductionmentioning

confidence: 61%

BET Bromodomain Proteins Regulate Transcriptional Reprogramming in Genetic Dilated Cardiomyopathy

Antolic

Wakimoto

Jing

et al. 2020

Preprint

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The bromodomain and extraterminal (BET) family of epigenetic reader proteins are key regulators of pathologic gene expression in the heart. Using mice carrying a human mutation in phospholamban (PLN R9C ) that develop progressive dilated cardiomyopathy (DCM), we previously identified the activation of inflammatory gene networks as a key early driver of DCM. We reasoned that BETs control this inflammatory process, representing a key node in the progression of genetic DCM. Using a chemical genetic strategy, PLN R9C or age-matched wild type mice were treated longitudinally with the BET inhibitor JQ1 or vehicle. JQ1 abrogated DCM, reduced cardiac fibrosis, and prolonged survival in PLN R9C mice by inhibiting inflammatory gene network expression at all disease stages. Cardiac fibroblast proliferation was also substantially reduced by JQ1. Interestingly, JQ1 had profound effects on pathologic gene network expression in cardiac fibroblasts, while having little effect on transcription in cardiomyocytes. Using co-immunoprecipitation, we identified BRD4 as a direct and essential regulator of NFB-mediated inflammatory gene transcription in cardiac fibroblasts. In this this model of chronic, heritable DCM, BETs activate inflammatory gene networks in cardiac fibroblasts via an NFB-dependent mechanism, marking them as critical effectors of pathologic gene expression.

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Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies

Cited by 34 publications

References 33 publications

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

BET Bromodomain Proteins Regulate Transcriptional Reprogramming in Genetic Dilated Cardiomyopathy

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