TY - JOUR
TI - Differences in molecular phenotype in mouse and human hypertrophic
cardiomyopathy
AU - Vakrou, Styliani
AU - Liu, Yamin
AU - Zhu, Li
AU - Greenland, Gabriela V.
AU - and Simsek, Bahadir
AU - Hebl, Virginia B.
AU - Guan, Yufan and
AU - Woldemichael, Kirubel
AU - Talbot, Conover C.
AU - Aon, Miguel A. and
AU - Fukunaga, Ryuya
AU - Abraham, M. Roselle
JO - Scientific Reports
PY - 2021
VL - 11
TODO - 1
SP - null
PB - Institute of Geographic Sciences and Natural Resources Research
SN - 2045-2322
TODO - 10.1038/s41598-021-89451-6
TODO - null
TODO - 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.
ER -