Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

Styliani Vakrou, Ryuya Fukunaga, D. Brian Foster, Lars Sorensen, Yamin Liu, Yufan Guan, Kirubel Woldemichael, Roberto Pineda-Reyes, Ting Liu, Jill C. Tardiff, Leslie A. Leinwand, Carlo G. Tocchetti, Theodore P. Abraham, Brian O'Rourke, Miguel A. Aon, M. Roselle Abraham

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation-bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti-TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number6
DOIs
StatePublished - Mar 22 2018

Keywords

  • Cardiology
  • Cardiovascular disease
  • Cell Biology
  • Mitochondria
  • Transcription

ASJC Scopus subject areas

  • Medicine(all)

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