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

Rau, Christoph; Romay, Milagros C.; Tuteryan, Mary; Wang, Jessica J.-C.; Santolini, Marc; Ren, Shuxun; Karma, Alain; Weiss, James N.; Wang, Yibin; Lusis, Aldons J.

doi:10.1016/j.cels.2016.10.016

Cited by 38 publications

(48 citation statements)

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“…Cardiac hypertrophy and HF have been associated with significant changes in the cardiac transcriptome, and altered expression of a number of mRNA transcripts and proteins have been associated with hypertrophy and HF. [13][14][15][16][17] It is clear, however, that complex diseases such as hypertrophy typically are caused not by alterations in a single mRNA or protein but rather by altered regulation of gene networks. 18,19 A systems biology approach to understand the development of and the sex differences in hypertrophy is needed.…”

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confidence: 99%

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

Harrington

Fillmore

Gao

et al. 2017

JAHA

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BackgroundHeart failure preceded by hypertrophy is a leading cause of death, and sex differences in hypertrophy are well known, although the basis for these sex differences is poorly understood.Methods and ResultsThis study used a systems biology approach to investigate mechanisms underlying sex differences in cardiac hypertrophy. Male and female mice were treated for 2 and 3 weeks with angiotensin II to induce hypertrophy. Sex differences in cardiac hypertrophy were apparent after 3 weeks of treatment. RNA sequencing was performed on hearts, and sex differences in mRNA expression at baseline and following hypertrophy were observed, as well as within‐sex differences between baseline and hypertrophy. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the mRNA differences induced by hypertrophy tended to overwhelm the sex differences. We performed an integrative analysis to identify mRNA networks that were differentially regulated in the 2 sexes by hypertrophy and obtained a network centered on PPARα (peroxisome proliferator‐activated receptor α). Mouse experiments further showed that acute inhibition of PPARα blocked sex differences in the development of hypertrophy.ConclusionsThe data in this study suggest that PPARα is involved in the sex‐dimorphic regulation of cardiac hypertrophy.

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A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

Harrington

Fillmore

Gao

et al. 2017

JAHA

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“…Indeed, Nppb is correlated to the fibrotic SAM genes in healthy mice, consistent with a regulatory homeostatic behavior, but is found among FC genes after betaadrenergic stimulation, consistent with a response proportionate to myocytes hypertrophy. It is also interesting to note that the SAM module overlaps significantly (p=3.4e-6, hypergeometric test) with a co-expression module previously found in post-ISO mice and shown to be involved in cardiac hypertrophy (38). Indeed, it shares the genes Timp1, Tnc, Mfap5, Col14a1 and Adamts2, the latter of which was validated experimentally as a regulator of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 58%

A personalized, multi-omics approach identifies genes involved in cardiac hypertrophy and heart failure

Santolini

Romay

Yukhtman

et al. 2017

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Identifying genes underlying complex diseases remains a major challenge. Biomarkers are typically identified by comparing average levels of gene expression in populations of healthy and diseased individuals. However, genetic diversities may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we leverage the Hybrid Mouse Diversity Panel (HMDP), a model system of 100+ genetically diverse strains of mice exhibiting different complex disease traits, to develop a personalized differential gene expression analysis that is able to identify disease-associated genes missed by traditional population-wide methods. The population-level and personalized approaches are compared for isoproterenol(ISO)-induced cardiac hypertrophy and heart failure using pre-and post-ISO gene expression and phenotypic data. The personalized approach identifies 36 Fold-Change (FC) genes predictive of the severity of cardiac hypertrophy, and enriched in genes previously associated with cardiac diseases in human. Strikingly, these genes are either up-or down-regulated at the individual strain level, and are therefore missed when averaging at the population level. Using insights from the gene regulatory network and proteinprotein interactome, we identify Hes1 as a strong candidate FC gene. We validate its role by showing that even a mild knockdown of 20-40% of Hes1 can induce a dramatic reduction of hypertrophy by 80-90% in rat neonatal cardiac cells. These findings emphasize the importance of a personalized approach to identify causal genes underlying complex diseases as well as to develop personalized therapies.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/120329 doi: bioRxiv preprint first posted online Mar. 24, 2017; Significance A traditional approach to investigate the genetic basis of complex diseases is to look for genes with a global change in expression between diseased and healthy individuals. Here, we investigate individual changes of gene expression by inducing heart failure in 100 strains of genetically distinct mice. We find that genes associated to the severity of the disease are either up-or down-regulated across individuals and are therefore missed by a traditional population level approach. However, they are enriched in human cardiac disease genes and form a coregulated module strongly interacting with a cardiac hypertrophic signaling network in the human interactome. Our analysis demonstrates that individualized approaches are crucial to reveal all genes involved in the development of complex diseases.peer-reviewed)

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“…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).…”

Section: Validation Of Genes Regulated By Glucose and Palmitic Acidmentioning

confidence: 67%

“…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.…”

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

Seldin

Kim

Romay

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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H728 -H741, 2017. First published February 24, 2017 doi:10.1152/ajpheart.00068.2016.-Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content. glucose; Trp53inp2; metabolic shift; hypertrophy IMPAIRED HEART METABOLISM has been shown as both contributory and causal to cardiac failure (45,57,60,61). The heart possesses a unique capacity to utilize a diverse array of substrates and shift preferences as a result of availability and/or disease state. Multiple studies have shown a clear association between heart failure (HF) and reduction of fatty acid oxidation machinery (36,38,47,54). To account for sustained energetic demands, this reduction in lipid oxidation is generally accompanied by increased glucose utilization (3,53,63). Although these phenomena have been described in detail, the specific mechanisms of cardiomyocyte substrate preference and utilization remain unclear.The relative contribution of this metabolic shift to a HF phenotype has been widely debated over the past few decades. Much of this debate has focused on differing observations as to the extent of glucose uptake (2, 71) and subsequent oxidation (1,11,14,31) in connection with HF. Many of these discrepancies are thought to be due to the complex etiology underlying HF and the various models used to assess it as well as the idiopathic progression of the disease (15,26,61,68).Here, we took a systems genetics approach to identify cardiomyocyte genes whose expressio...

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

Cited by 38 publications

References 57 publications

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

A personalized, multi-omics approach identifies genes involved in cardiac hypertrophy and heart failure

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

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