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A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure.

ABSTRACT: A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100?+?strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those "fold-change" genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.

SUBMITTER: Santolini M

PROVIDER: S-EPMC5825397 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure.

Santolini Marc M Romay Milagros C MC Yukhtman Clara L CL Rau Christoph D CD Ren Shuxun S Saucerman Jeffrey J JJ Wang Jessica J JJ Weiss James N JN Wang Yibin Y Lusis Aldons J AJ Karma Alain A

NPJ systems biology and applications 20180224

A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mic ...[more]

PMID: 29507758

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Project description:BackgroundPathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.MethodsA screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.ResultsAmong 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.ConclusionOur data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.

Project description:Under stress, the heart undergoes extensive remodeling resulting in cardiac fibrosis and hypertrophy, ultimately contributing to chronic heart failure (CHF). Alterations in microRNA levels are associated with dysfunctional gene expression profiles involved in the pathogenesis of heart failure. We previously showed that myocardial infarction-induced microRNA-enriched extracellular vesicles (EVs) contribute to the reduction in antioxidant enzymes by targeting Nrf2 signaling in CHF. MicroRNA-27a (miRNA-27a) is the predominant microRNA contained in cardiac fibroblast-derived EVs contributing to oxidative stress along with hypertrophic gene expression in cardiomyocytes. In the present study, we observed that miRNA-27a passenger strand (miRNA-27a*) was markedly upregulated in the non-infarcted area of the left ventricle of rats with CHF and encapsulated into EVs and secreted into the circulation. Bioinformatic analysis revealed that PDZ and LIM domain 5 (PDLIM5) is one of the major targets of miRNA-27a*, playing a major role in cardiac structure and function, and potentially contributing to the progression of cardiac hypertrophy. Our in vivo data demonstrate that PDLIM5 is down-regulated in the progression of heart failure, accompanied with the upregulation of hypertrophic genes and consistent with alterations in miRNA-27a*. Moreover, exogenous administration of miRNA27a* mimics inhibit PDLIM5 translation in cardiomyocytes whereas a miRNA27a* inhibitor enhanced PDLIM5 expression. Importantly, we confirmed that infarcted hearts have higher abundance of miRNA-27a* in EVs compared to normal hearts and further demonstrated that cultured cardiac fibroblasts secrete miRNA27a*-enriched EVs into the extracellular space in response to Angiotensin II stimulation, which inhibited PDLIM5 translation, leading to cardiomyocyte hypertrophic gene expression. In vivo studies suggest that the administration of a miRNA-27a* inhibitor in CHF rats partially blocks endogenous miR-27a* expression, prevents hypertrophic gene expression and improves myocardial contractility. These findings suggest that cardiac fibroblast-secretion of miRNA27a*-enriched EVs may act as a paracrine signaling mediator of cardiac hypertrophy that has potential as a novel therapeutic target.

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A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure.

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A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure.

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