RNA-seq profiling of mRNA associated with hypertrophic cardiomyopathy

Ren, Changwei; Liu, Jiaji; Li, Jinhua; Li, Jingwei; Dai, Jiang; Lai, Yongqiang

doi:10.3892/mmr.2016.5931

Cited by 18 publications

(29 citation statements)

References 35 publications

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“…These differences could be the result of a myriad of factors including age, expression of disease-modifying genes, epigenetics modifiers, miRNAs and lncRNAs [ 61 , 64 ]. The use of large-scale transcriptomic analyses from isogenic sets of hiPSC-CMs [ 65 ] may uncover new drug targets, including gene modifiers who remain unexplored.…”

Section: Discussionmentioning

confidence: 99%

Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics

Bhagwan

Mosqueira

Chairez‐Cantu

et al. 2020

Journal of Molecular and Cellular Cardiology

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Background Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular condition. Despite being strongly associated with genetic alterations, wide variation of disease penetrance, expressivity and hallmarks of progression complicate treatment. We aimed to characterize different human isogenic cellular models of HCM bearing patient-relevant mutations to clarify genetic causation and disease mechanisms, hence facilitating the development of effective therapeutics. Methods We directly compared the p.β-MHC-R453C and p.ACTC1-E99K HCM-associated mutations in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and their healthy isogenic counterparts, generated using CRISPR/Cas9 genome editing technology. By harnessing several state-of-the-art HCM phenotyping techniques, these mutations were investigated to identify similarities and differences in disease progression and hypertrophic signaling pathways, towards establishing potential targets for pharmacological treatment. CRISPR/Cas9 knock-in of the genetically-encoded calcium indicator R-GECO1.0 to the AAVS1 locus into these disease models resulted in calcium reporter lines. Results Confocal line scan analysis identified calcium transient arrhythmias and intracellular calcium overload in both models. The use of optogenetics and 2D/3D contractility assays revealed opposing phenotypes in the two mutations. Gene expression analysis highlighted upregulation of CALM1, CASQ2 and CAMK2D, and downregulation of IRF8 in p.β-MHC-R453C mutants, whereas the opposite changes were detected in p.ACTC1-E99K mutants. Contrasting profiles of nuclear translocation of NFATc1 and MEF2 between the two HCM models suggest differential hypertrophic signaling pathway activation. Calcium transient abnormalities were rescued with combination of dantrolene and ranolazine, whilst mavacamten reduced the hyper-contractile phenotype of p.ACTC1-E99K hiPSC-CMs. Conclusions Our data show that hypercontractility and molecular signaling within HCM are not uniform between different gene mutations, suggesting that a ‘one-size fits all’ treatment underestimates the complexity of the disease. Understanding where the similarities (arrhythmogenesis, bioenergetics) and differences (contractility, molecular profile) lie will allow development of therapeutics that are directed towards common mechanisms or tailored to each disease variant, hence providing effective patient-specific therapy.

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Section: Discussionmentioning

confidence: 99%

Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics

Bhagwan

Mosqueira

Chairez‐Cantu

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…Because this was a retrospective study, we were not able to correlate FBLN2 levels in tissues and their corresponding associated cells because, according to unshown data, this requires sampling of the fibroblasts from multiple trackable tissue regions. This and the study of proteomes and transcriptomes will be the subject of a future investigation [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

An Investigation of Fibulin-2 in Hypertrophic Cardiomyopathy

Ibrahim

Roshdy

Elshorbagy

et al. 2020

IJMS

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Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease, with a prevalence of at least 1 in 500 in the general population. The disease is pleiotropic and is characterized by an increased stiffness of the myocardium, partly due to changes in the extracellular matrix (ECM), with elevated levels of interstitial fibrosis. Myocardial fibrosis is linked to impaired diastolic function and possibly phenotypic heterogeneity of HCM. The ECM consists of a very large number of proteins, which actively interact with each other as well as with myocardial cells. The role of other multiple components of the ECM in HCM has not been defined. Fibulin-2 is a glycoprotein component of the ECM, which plays an important role during embryogenesis of the heart; however, its role in adult myocardium has not been adequately studied. We here describe, for the first time, abnormal expression of fibulin-2 in the myocardium in patients with HCM as compared to normal controls. This abnormal expression was localized in the cytoplasm of myocardial cells and in the interstitial fibroblasts. In addition, fibulin-2 levels, measured by ELISA, were significantly elevated in the serum of patients with HCM as compared to normal controls.

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“…Importantly, transcriptomic data are available and are expected to highlight new molecular targets for therapy. Two reports have performed RNA sequencing analysis from nongenetically profiled patient-derived tissue explants, identifying hundreds of differentially expressed genes relative to unrelated healthy controls [112,113]. Data on transcriptomic analysis of isogenic sets of HCM hPSC-CM lines have recently been published [81,114] providing genetically precise comparisons for identifying new molecular mechanisms of disease.…”

Section: Discussionmentioning

confidence: 99%