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2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced
Heart Failure Mouse Model
Presenter: Jessica Jen-Chu Wang
Division: Cardiology
☒ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other
Principal Investigator/Mentor: Aldons J. Lusis
Thematic Poster Category:
Co-Investigators: Yibin Wang
Genetic Diseases, Gene-Environment Interactions, Gene Therapy
Abstract
We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced
heart failure model in mice, which allowed control of confounding factors in an experimental setting.
We characterized the changes in cardiac structure and function in response to chronic isoproterenol
infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac
structure and function, whether under normal or stress conditions, has a strong genetic component,
with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of
cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17
genome-wide significant loci, including several loci containing previously implicated genes. Cardiac
tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation,
and coding sequencing variation analyses were performed to prioritize candidate genes and to
generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a
novel gene, Myh14, as a negative regulator of isoproterenol-induced left ventricular mass hypertrophy
in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal
gene Nppb, and fibrosis gene Lgals3 in isoproterenol-treated Myh14 deficient hearts compared to
controls.