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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
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Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy
Styliani Vakrou1,2, Ryuya Fukunaga3, D Brian Foster2
1Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, Maryland, USA.
JCI Insight
|March 23, 2018
Summary
Hypertrophic cardiomyopathy (HCM) research reveals distinct molecular profiles in early-stage disease models. Genotype-specific differences in cellular function and signaling pathways inform potential precision therapies for HCM.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) arises from sarcomeric protein mutations, leading to varied cellular signaling and pathology.
- Current clinical trials often group HCM patients by diagnosis, overlooking genotype-specific differences.
- Understanding early-stage molecular distinctions is crucial for developing targeted therapies.
Purpose of the Study:
- To compare cellular/mitochondrial function and molecular biosignatures in two distinct mouse models of HCM at an early disease stage.
- To identify genotype-specific differences in signaling pathways and cellular responses.
- To explore potential therapeutic strategies based on molecular profiles.
Main Methods:
- Comparative analysis of transcriptome and miRNome between R92W-TnT and R403Q-αMyHC mutant HCM mouse models.
- Assessment of intracellular redox environment and mitochondrial function, including antioxidant defenses and permeability transition pore opening.
- Pathway analysis of sequencing data to identify key molecular signaling differences.
Main Results:
- Significant differences observed in transcriptome, miRNome, redox environment, and mitochondrial function between the two HCM models.
- R92W-TnT mutants displayed a molecular signature indicative of activated profibrotic transforming growth factor-beta (TGF-β) signaling.
- Oxidative stress and mitochondrial impairment in R92W-TnT mice correlated with TGF-β pathway activation.
Conclusions:
- Early-stage molecular and functional profiling reveals distinct pathogenic mechanisms in different HCM genotypes.
- The R92W-TnT mutation is associated with TGF-β pathway activation, suggesting potential therapeutic targets.
- Precision medicine approaches, including angiotensin receptor blockers and mitochondrial antioxidants, may benefit specific HCM patient groups.
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