Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.
This study investigated whether activating estrogen-related receptors (ERRα and ERRγ) — key regulators of cardiac metabolism — could treat heart failure (HF). Researchers designed two novel pan-ERR agonist compounds, SLU-PP-332 and SLU-PP-915, using structure-based drug design, and tested them in a mouse model of pressure overload-induced HF. Both compounds significantly improved ejection fraction, reduced cardiac fibrosis, and increased survival in mice without causing additional cardiac hypertrophy. Multi-omics analyses (RNA sequencing and metabolomics) revealed that ERR agonists broadly activated metabolic gene programs — particularly those governing fatty acid oxidation and mitochondrial function — and substantially normalized disrupted metabolic profiles in failing hearts. In vitro and in vivo genetic dependency experiments identified ERRγ as the primary mediator of these cardioprotective effects and confirmed target specificity. The study also found that ERR agonism downregulated cell cycle and developmental pathways, partly via the transcription factor E2F1. Limitations include that all in vivo work was conducted in mice, and no human data were presented. The authors conclude that ERR agonists represent a promising pharmacologic strategy for HF, warranting further development.
Why this grade: All in vivo efficacy data were generated exclusively in a mouse pressure-overload heart failure model with no human subjects or clinical data included.
Background Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. Methods Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. Results Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. Conclusions ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.
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