Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model

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 sequence 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 ISO-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 ISO-treated Myh14 deficient hearts compared to controls.

Alterations in sarcomere function modify the hyperplastic to hypertrophic transition phase of mammalian cardiomyocyte development

“…The MYBPC3-truncation mouse model was in a 129SvEv genetic background and our MYBPC3 models were bred in a C57BL/6 genetic background. Different inbred mouse strains have been reported to have unique cardiovascular responses to pathological stimuli (42,43). Likewise, different inbred mouse strains have been shown to have divergent regenerative capabilities (e.g., the MRL line), suggesting cell cycle regulation may be modified by genetic background (44).…”

Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice

“…Progeny were then studied for HF traits following ISO treatment as previously described (Rau et al, 2015b; Wang et al, 2016). Briefly, Isoproterenol (30 mg per kg body weight per day) was administered for 21 days in 8–10 week old female mice using ALZET osmotic mini-pumps, which were surgically implanted intraperitoneally.…”

“…We recently applied this approach to identify loci and genes that contribute to HF traits in an isoproterenol (ISO) model, which mimics the chronic β-adrenergic stimulation that often occurs in human HF. Association analyses identified both known and novel genes contributing to hypertrophy, cardiac fibrosis, and echocardiographic traits (Rau et al, 2015b; Wang et al, 2016). …”

A systems genetics approach identifiesTrp53inp2as a link between cardiomyocyte glucose utilization and hypertrophic response

“…where Ͼ100 strains were administered isoproterenol-loaded osmotic pumps for 3 wk to model the pathophysiology of heart failure (51,52,69). Here, we observed dramatic and robust responses to isoproterenol, which mirrored hypertrophy, substantial remodeling, and other relevant perturbations commonly observed in human heart failure (8,21).…”

“…We surveyed a panel of 100 inbred strains that we examined previously for global transcript levels either untreated or treated for 3 wk with isoproterenol. Isoproterenol was used to mimic the catecholamine-driven cardiac hypertrophy and pathological remodeling (51,69). We first screened untreated mice for substrate-specific cardiomyocyte candidate genes based on heart transcriptional profiles and circulating nutrients.…”