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Peer-reviewedCC BYClinical science (London, England : 1979)

Adropin protects against cardiac remodeling and metabolic dysfunction in a male mouse HFpEF model

  • Bellina A.S. Mushala1,2,3
  • Michael W. Stoner1,2,3
  • Maryam Sharifi-Sanjani1,2,3
  • Janet R. Manning1,2,3
  • Paramesha Bugga1,2,3
  • Nisha Bhattarai1,2,3
  • Brenda McMahon1
  • Amber Vandevender2,4
  • Steven J. Mullet5
  • Brett A. Kaufman1,2,3
  • Sruti S. Shiva1,2,6
  • Cheng Zhang7
5 more authors
  • Eric S. Goetzman8
  • Stephen Y. Chan1,3
  • Stacy L. Gelhaus7,5
  • Michael J. Jurczak2,4
  • Iain Scott1,2,3
8 affiliations
  1. 1Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261
  2. 2Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15261
  3. 3Division of Cardiology, University of Pittsburgh, Pittsburgh, PA 15261
  4. 4Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15261
  5. 5Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15261
  6. 6Division of Classical Hematology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
  7. 7Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261
  8. 8Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261
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Abstract

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a heterogenous metabolic disease, which in the heart presents as left ventricle diastolic dysfunction, ventricular stiffness, and myocardial structural remodeling. Deleterious changes in cardiac metabolism are central to HFpEF pathophysiology, and proposed treatments for the disease have focused on repairing these defects. In this study, we used a preclinical mouse model that recapitulates cardiometabolic HFpEF to elucidate the molecular mechanisms driving cardiac dysfunction, and tested whether recombinant Adropin (a liver- and brain-derived endogenous peptide hormone) could reverse observed defects. We show that long-term treatment with Adropin reversed multiple markers of HFpEF-related cardiac dysfunction (including fibrosis, diastolic dysfunction, and cardiomyocyte hypertrophy). Using untargeted metabolomics, we found that Adropin treatment reduced hexosamine biosynthesis pathway activity, leading to a reduction in the O-GlcNAcylation of the cardiac fatty acid oxidation enzyme long chain acyl-CoA dehydrogenase (LCAD). Reducing LCAD O-GlcNAcylation increased LCAD activity in vitro , and reduced the accumulation of long-chain acylcarnitines in HFpEF mouse hearts in vivo. Our results suggest that Adropin may restore cardiac metabolic function in HFpEF, and that targeting this pathway may be a novel therapeutic avenue for this disease. CLINICAL PERSPECTIVE - Adropin is a circulating liver- and brain-derived peptide that regulates energy metabolism in the heart and other high metabolic-demand tissues. The plasma abundance of Adropin is decreased in diabetic, hypertensive, and aged individuals; all comorbid risk factors for the development of heart failure with preserved ejection (HFpEF). We therefore examined the potential role of Adropin in HFpEF pathophysiology. - Patients with HFpEF display significant reductions in circulating Adropin levels, matching those seen in comorbid diseases. In a mouse model of HFpEF, treatment with recombinant Adropin reduced diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy. - These data suggest that targeting the Adropin pathway may represent a new therapeutic approach in HFpEF.

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Cite

BibTeXRIS
BibTeX
@article{mushala2026adropin,
  title = {{Adropin protects against cardiac remodeling and metabolic dysfunction in a male mouse HFpEF model}},
  author = {Bellina A.S. Mushala and Michael W. Stoner and Maryam Sharifi-Sanjani and Janet R. Manning and Paramesha Bugga and Nisha Bhattarai and Brenda McMahon and Amber Vandevender and Steven J. Mullet and Brett A. Kaufman and Sruti S. Shiva and Cheng Zhang and Eric S. Goetzman and Stephen Y. Chan and Stacy L. Gelhaus and Michael J. Jurczak and Iain Scott},
  journal = {Clinical science (London, England : 1979)},
  year = {2026},
  month = jul,
  doi = {10.1042/cs20261501},
  url = {https://doi.org/10.1042/cs20261501},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Adropin protects against cardiac remodeling and metabolic dysfunction in a male mouse HFpEF model
AU  - Bellina A.S. Mushala
AU  - Michael W. Stoner
AU  - Maryam Sharifi-Sanjani
AU  - Janet R. Manning
AU  - Paramesha Bugga
AU  - Nisha Bhattarai
AU  - Brenda McMahon
AU  - Amber Vandevender
AU  - Steven J. Mullet
AU  - Brett A. Kaufman
AU  - Sruti S. Shiva
AU  - Cheng Zhang
AU  - Eric S. Goetzman
AU  - Stephen Y. Chan
AU  - Stacy L. Gelhaus
AU  - Michael J. Jurczak
AU  - Iain Scott
PY  - 2026
DA  - 2026/07/15
JO  - Clinical science (London, England : 1979)
DO  - 10.1042/cs20261501
UR  - https://doi.org/10.1042/cs20261501
AB  - Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a heterogenous metabolic disease, which in the heart presents as left ventricle diastolic dysfunction, ventricular stiffness, and myocardial structural remodeling. Deleterious changes in cardiac metabolism are central to HFpEF pathophysiology, and proposed treatments for the disease have focused on repairing these defects. In this study, we used a preclinical mouse model that recapitulates cardiometabolic HFpEF to elucidate the molecular mechanisms driving cardiac dysfunction, and tested whether recombinant Adropin (a liver- and brain-derived endogenous peptide hormone) could reverse observed defects. We show that long-term treatment with Adropin reversed multiple markers of HFpEF-related cardiac dysfunction (including fibrosis, diastolic dysfunction, and cardiomyocyte hypertrophy). Using untargeted metabolomics, we found that Adropin treatment reduced hexosamine biosynthesis pathway activity, leading to a reduction in the O-GlcNAcylation of the cardiac fatty acid oxidation enzyme long chain acyl-CoA dehydrogenase (LCAD). Reducing LCAD O-GlcNAcylation increased LCAD activity in vitro , and reduced the accumulation of long-chain acylcarnitines in HFpEF mouse hearts in vivo. Our results suggest that Adropin may restore cardiac metabolic function in HFpEF, and that targeting this pathway may be a novel therapeutic avenue for this disease. CLINICAL PERSPECTIVE - Adropin is a circulating liver- and brain-derived peptide that regulates energy metabolism in the heart and other high metabolic-demand tissues. The plasma abundance of Adropin is decreased in diabetic, hypertensive, and aged individuals; all comorbid risk factors for the development of heart failure with preserved ejection (HFpEF). We therefore examined the potential role of Adropin in HFpEF pathophysiology. - Patients with HFpEF display significant reductions in circulating Adropin levels, matching those seen in comorbid diseases. In a mouse model of HFpEF, treatment with recombinant Adropin reduced diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy. - These data suggest that targeting the Adropin pathway may represent a new therapeutic approach in HFpEF.
SN  - 0143-5221
SN  - 1470-8736
ER  -