Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy

Prestes, Priscilla; Marques, Francine Z.; López–Campos, Guillermo; Lewandowski, Paul; Delbridge, L.; Charchar, Fadi J.; Harrap, Stephen

doi:10.1152/physiolgenomics.00143.2017

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…Familial hypertrophic cardiomyopathy is most commonly linked with single-point sarcomeric mutations. In contrast, the rat model used in the present study is characterized by polygenic disruption causing cardiomyocyte early terminal differentiation and compensatory hypertrophy ( Porrello et al, 2009a ; Prestes et al, 2018 ). In addition, direct comparison of in vitro tissue efficiency and in vivo whole-heart efficiency requires careful consideration.…”

Section: Discussionmentioning

confidence: 96%

Cardiac mechanical efficiency is preserved in primary cardiac hypertrophy despite impaired mechanical function

Han

Tran

Crossman

et al. 2021

Journal of General Physiology

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Increased heart size is a major risk factor for heart failure and premature mortality. Although abnormal heart growth subsequent to hypertension often accompanies disturbances in mechano-energetics and cardiac efficiency, it remains uncertain whether hypertrophy is their primary driver. In this study, we aimed to investigate the direct association between cardiac hypertrophy and cardiac mechano-energetics using isolated left-ventricular trabeculae from a rat model of primary cardiac hypertrophy and its control. We evaluated energy expenditure (heat output) and mechanical performance (force length work production) simultaneously at a range of preloads and afterloads in a microcalorimeter, we determined energy expenditure related to cross-bridge cycling and Ca2+ cycling (activation heat), and we quantified energy efficiency. Rats with cardiac hypertrophy exhibited increased cardiomyocyte length and width. Their trabeculae showed mechanical impairment, evidenced by lower force production, extent and kinetics of shortening, and work output. Lower force was associated with lower energy expenditure related to Ca2+ cycling and to cross-bridge cycling. However, despite these changes, both mechanical and cross-bridge energy efficiency were unchanged. Our results show that cardiac hypertrophy is associated with impaired contractile performance and with preservation of energy efficiency. These findings provide direction for future investigations targeting metabolic and Ca2+ disturbances underlying cardiac mechanical and energetic impairment in primary cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 96%

Cardiac mechanical efficiency is preserved in primary cardiac hypertrophy despite impaired mechanical function

Han

Tran

Crossman

et al. 2021

Journal of General Physiology

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“…conduction system diseases, atrial fibrillation, and ventricular tachycardia) are the main clinical signs that occur after the accumulation of misfolded TTR protein (52-54). Furthermore, transcriptomic interaction is observed between TTR and DSG2 to induce hypertrophic cardiomyopathy in animal models (55). In this context, methylation changes in DSC2 and DSG2 genes could reflect pathogenic processes in hATTR target organs.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic profiling of Italian patients identified methylation sites associated with hereditary Transthyretin amyloidosis

Lillo

Pathak

Angelis

et al. 2020

Preprint

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Hereditary Transthyretin (TTR) Amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing i) TTR coding mutation carriers vs. non-carriers, and ii) Val30Met (rs28933979) carriers vs. carriers of other TTR mutations. In the first analysis, we observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (beta =-0.60, p=6.26x10-8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology:0050435, q=0.007), amyloid fiber formation (Reactome HSA-977225, q=0.008), and Alzheimers disease (KEGG hsa05010, q=2.2x10-4). Additionally, TTR and BACE2 share APP (Amyloid-beta precursor protein) as a validated protein interactor. In the second analysis, we observed that Val30Met carriers have a significant hypomethylation at cg13139646 site located in TTR exonic region (beta=-2.18, p=3.34x10-11). A methylation quantitative trait locus analysis considering a 20 Kb region including TTR coding and non-coding regions suggested that TTR coding variants (Ile68Leu, rs121918085; Ala120Ser, rs876658108; Gly6Ser, rs1800458) have independent effects on cg13139646 methylation, while no independent effect was observed for non-coding variants. In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

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“…A previous microarray analysis on human serum revealed several circulating miRNAs, including miR-18a-5p, miR-30d-5p, miR-21-5p, miR-193-5p, miR-10b-5p, miR-15a-5p, miR-296-5p, and miR-29a-3p, were potential diagnostic biomarkers for diffuse myocardial fibrosis during HCM (13). Moreover, Prestes et al (14) reported a validated miRNA-mRNA network composed of two upregulated miRNAs, miR-34a-5p and miR-17-5p, and five targeted genes including Pkp2, Rbm20, Ryr2, Tpm1, and Vcl in hypertrophic heart rat. Yet so far, no systemic and detailed analysis of miRNA-mRNA regulatory network was conducted to improve the diagnostic method of HCM.…”

Section: Introductionmentioning

confidence: 96%

Identification of Potential miRNA-mRNA Regulatory Network Contributing to Hypertrophic Cardiomyopathy (HCM)

Wang

2021

Front. Cardiovasc. Med.

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Background: Hypertrophic cardiomyopathy (HCM) is a myocardial disease with unidentified pathogenesis. Increasing evidence indicated the potential role of microRNA (miRNA)-mRNA regulatory network in disease development. This study aimed to explore the miRNA-mRNA axis in HCM.Methods: The miRNA and mRNA expression profiles obtained from the Gene Expression Omnibus (GEO) database were used to identify differentially expressed miRNAs (DEMs) and genes (DEGs) between HCM and normal samples. Target genes of DEMs were determined by miRTarBase. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to identify biological functions of the DEGs and DEMs. miRNA-mRNA regulatory network was constructed to identify the hub genes and miRNAs. Logistic regression model for HCM prediction was established basing on the network.Results: A total of 224 upregulated and 366 downregulated DEGs and 10 upregulated and 14 downregulated DEMs were determined. We identified 384 DEM-targeted genes, and 20 of them were overlapped with the DEGs. The enriched functions include extracellular structure organization, organ growth, and phagosome and melanoma pathways. The four miRNAs and three mRNAs, including hsa-miR-373, hsa-miR-371-3p, hsa-miR-34b, hsa-miR-452, ARHGDIA, SEC61A1, and MYC, were identified through miRNA-mRNA regulatory network to construct the logistic regression model. The area under curve (AUC) values over 0.9 suggested the good performance of the model.Conclusion: The potential miRNA-mRNA regulatory network and established logistic regression model in our study may provide promising diagnostic methods for HCM.

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Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy

Cited by 5 publications

References 37 publications

Cardiac mechanical efficiency is preserved in primary cardiac hypertrophy despite impaired mechanical function

Cardiac mechanical efficiency is preserved in primary cardiac hypertrophy despite impaired mechanical function

Epigenetic profiling of Italian patients identified methylation sites associated with hereditary Transthyretin amyloidosis

Identification of Potential miRNA-mRNA Regulatory Network Contributing to Hypertrophic Cardiomyopathy (HCM)

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