2. Academic Validation
  3. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

  • Circulation. 2023 Nov 14. doi: 10.1161/CIRCULATIONAHA.123.066542.
Weiyi Xu # 1,  Cyrielle Billon # 2 3,  Hui Li 1,  Andrea Wilderman 1,  Lei Qi 1,  Andrea Graves 1,  Jernie Rae Dela Cruz Rideb 1,  Yuanbiao Zhao 1,  Matthew Hayes 2 3,  Keyang Yu 1,  McKenna Losby 1,  Carissa S Hampton 4,  Christiana M Adeyemi 4,  Seok Jae Hong 5,  Eleni Nasiotis 1,  Chen Fu 6,  Tae Gyu Oh 7,  Weiwei Fan 7,  Michael Downes 7,  Ryan D Welch 8,  Ronald M Evans 7,  Aleksandar Milosavljevic 1,  John K Walker 4,  Brian C Jensen 5 9,  Liming Pei 10,  Thomas Burris 2 3,  Lilei Zhang 1
Affiliations

Affiliations

  • 1 Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX (W.X., H.L., A.W., L.Q., A.G., J.R.D.C.R., Y.Z., K.Y., M.L., E.N., A.M., L.Z.).
  • 2 Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St Louis, MO (C.B., M.H., T.B.).
  • 3 Center for Clinical Pharmacology, St Louis College of Pharmacy, Washington University School of Medicine, St Louis, MO (C.B., M.H., T.B.).
  • 4 Department of Pharmacology and Physiology, St Louis University School of Medicine, MO (C.S.H., C.M.A., J.K.W.).
  • 5 McAllister Heart Institute (S.J.H., B.C.J.).
  • 6 University Hospitals Cleveland Medical Center, OH (C.F.).
  • 7 Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA (T.G.O., W.F., M.D., R.M.E.).
  • 8 Biology and Chemistry Department, Blackburn College, Carlinville, IL (R.D.W.).
  • 9 Department of Medicine, Division of Cardiology (B.C.J.), University of North Carolina, Chapel Hill.
  • 10 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia (L.P.).
  • # Contributed equally.
PMID: 37961903 DOI: 10.1161/CIRCULATIONAHA.123.066542
Abstract

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.

Keywords

cell cycle; heart failure; metabolism.

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