Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models
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Author
Vakrou, StylianiFukunaga, Ryuya
Foster, D Brian
Sorensen, Lars
Liu, Yamin
Guan, Yufan
Woldemichael, Kirubel
Pineda-Reyes, Roberto
Liu, Ting
Tardiff, Jill C
Leinwand, Leslie A
Tocchetti, Carlo G
Abraham, Theodore P
O'Rourke, Brian
Aon, Miguel A
Abraham, M Roselle
Affiliation
Univ Arizona, Eller Coll ManagementIssue Date
2018-03-22
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AMER SOC CLINICAL INVESTIGATION INCCitation
JCI Insight. 2018;3(6):e94493. https://doi.org/10.1172/jci.insight.94493.Journal
JCI INSIGHTRights
Copyright © 2018, American Society for Clinical Investigation.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.ISSN
2379-3708PubMed ID
29563334Version
Final published versionSponsors
John Taylor Babbitt (JTB) foundation; NIH grant [R01HL092985]; UCSF Division of Cardiology; American Heart Association [15SDG23220028]; National Institute of General Medical Sciences (NIGMS) [R01GM116841]; Johns Hopkins University Department of Biological Chemistry; Hellenic Cardiology Society; NIH Diversity Supplement; Wuxi Mei-Yuan Hospital, China; NIH [HL11738]ae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.94493
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