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Epigenome-Wide DNA Methylation Profiling in Comparison between Pathological and Physiological Hypertrophy of Human Cardiomyocytes

ABSTRACT: Physiological and pathological stimuli result in distinct anatomic forms of cardiac hypertrophy, but the head-to-head comparison of molecular regulation between physiological and pathological cardiac hypertrophy is less well understood, especially at the DNA methylation level. We conducted an in vitro study using human cardiomyocyte cell line AC16 exposed to angiotensin II (AngII) and insulin-like growth factor 1 (IGF-1) to mimic pathologically and physiologically hypertrophic heart models, respectively. Whole genome DNA methylation patterns were profiled by the Infinium human MethylationEPIC platform with >850K DNA methylation loci. We detected 194 loci that are significantly differentially methylated after AngII treatment (vs control) with 50.0% hypermethylated, and 206 significant loci after IGF-1 treatment (vs control) with 45.1% hypermethylated (Adjusted P < 0.05). Mapping the significant loci to genes, we identified 158 genes corresponding to AngII treatment and 175 genes to IGF-1 treatment, with 67 genes overlapping between AngII and IGF-1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241551 | GEO | 2023/10/03

REPOSITORIES: GEO

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Project description:Aims: Pathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. Methods and Results: Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP)3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. Conclusion: In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.

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Epigenome-Wide DNA Methylation Profiling in Comparison between Pathological and Physiological Hypertrophy of Human Cardiomyocytes

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