Περίληψη:
Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic
heterogeneity. We investigated the molecular basis of the cardiac
phenotype in two mouse models at established disease stage (mouse-HCM),
and human myectomy tissue (human-HCM). We analyzed the transcriptome in
2 mouse models with non-obstructive HCM (R403Q-MyHC,
R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy
tissue of patients with obstructive HCM/control hearts (GSE36961,
GSE36946). Additionally, we examined myocyte redox, cardiac
mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS
generation/scavenging and mt-Ca2+ handling in mice. We identified
distinct allele-specific gene expression in mouse-HCM, and marked
differences between mouse-HCM and human-HCM. Only two genes (CASQ1,
GPT1) were similarly dysregulated in both mutant mice and human-HCM. No
signaling pathway or transcription factor was predicted to be similarly
dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and
human-HCM. Losartan was a predicted therapy only in TnT-mutant mice.
KEGG pathway analysis revealed enrichment for several metabolic
pathways, but only pyruvate metabolism was enriched in both mutant mice
and human-HCM. Both mutant mouse myocytes demonstrated evidence of an
oxidized redox environment. Mitochondrial complex I RCR was lower in
both mutant mice compared to controls. MyHC-mutant mice had similar
mtDNA-CN and mt-Ca2+ handling, but TnT-mutant mice exhibited lower
mtDNA-CN and impaired mt-Ca2+ handling, compared to littermate-controls.
Molecular profiling reveals differences in gene expression,
transcriptional regulation, intracellular signaling and
mt-number/function in 2 mouse models at established disease stage.
Further studies are needed to confirm differences in gene expression
between mouse and human-HCM, and to examine whether cardiac phenotype,
genotype and/or species differences underlie the divergence in molecular
profiles.
Συγγραφείς:
Vakrou, Styliani
Liu, Yamin
Zhu, Li
Greenland, Gabriela V.
and Simsek, Bahadir
Hebl, Virginia B.
Guan, Yufan and
Woldemichael, Kirubel
Talbot, Conover C.
Aon, Miguel A. and
Fukunaga, Ryuya
Abraham, M. Roselle
