2. Academic Validation
  3. Dysregulated Protein s-Nitrosylation Promotes Nitrosative Stress and Disease Progression in Heart Failure With Preserved Ejection Fraction

Dysregulated Protein s-Nitrosylation Promotes Nitrosative Stress and Disease Progression in Heart Failure With Preserved Ejection Fraction

  • Circ Res. 2025 Oct 10;137(9):1185-1206. doi: 10.1161/CIRCRESAHA.124.326042.
Zhen Li 1 2,  Kyle B LaPenna 3,  Natalie D Gehred 4,  Xiaoman Yu 1 2,  W H Wilson Tang 5 6,  Jake E Doiron 3,  Huijing Xia 3,  Jingshu Chen 7,  Ian H Driver 7,  Frank B Sachse 7,  Naoto Muraoka 7,  Antonia Katsouda 8 9,  Paraskevas Zampas 8 9,  Amelia G Haydel 3,  Heather Quiriarte 10,  Timothy D Allerton 10,  Alexia Zagouras 5 6,  Jennifer Wilcox 6,  Tatiana Gromova 4,  Yueqin Zheng 11,  Andreas Papapetropoulos 8 9,  Sanjiv J Shah 12,  Traci T Goodchild 2,  Martin B Jensen 7,  Thomas E Sharp 3rd 13,  Thomas M Vondriska 4,  David J Lefer 2
Affiliations

Affiliations

  • 1 School of Traditional Chinese Pharmacy (Z.L., X.Y.), China Pharmaceutical University, Nanjing, China.
  • 2 Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (Z.L., X.Y., T.T.G., D.J.L.).
  • 3 Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans (K.B.L.P., J.E.D., H.X., A.G.H.).
  • 4 Departments of Anesthesiology and Perioperative Medicine, Medicine and Physiology, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles (N.D.G., T.G., T.M.V.).
  • 5 Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute (W.H.W.T., A.Z.), Cleveland Clinic, OH.
  • 6 Department of Cardiovascular and Metabolic Sciences, Center of Microbiome and Human Health (W.H.W.T., A.Z., J.W.), Cleveland Clinic, OH.
  • 7 Gordian Biotechnology, South San Francisco, CA (J.C., I.H.D., F.B.S., N.M., M.B.J.).
  • 8 Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece (A.K., P.Z., A.P.).
  • 9 Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Greece (A.K. P.Z., A.P.).
  • 10 Vascular Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA (H.Q., T.D.A.).
  • 11 State Key Laboratory of Natural Medicine, Center of Drug Discovery (Y.Z.), China Pharmaceutical University, Nanjing, China.
  • 12 Northwestern University Medicine, Feinberg School of Medicine, Chicago, IL (S.J.S.).
  • 13 Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL (T.E.S.).
PMID: 40959880 DOI: 10.1161/CIRCRESAHA.124.326042
Abstract

Background: Recent studies suggest aberrant elevation of iNOS (inducible NO Synthase) expression and excessive protein s-nitrosylation promote the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, the interplay between NO bioavailability, enzymatic regulation of protein s-nitrosylation by transnitrosylase and denitrosylase, and HFpEF progression remains poorly defined. We investigated the molecular basis of nitrosative stress in HFpEF, focusing on alterations in NO signaling and regulation of protein s-nitrosylation.

Methods: Circulating nitrite (NO bioavailability) and nitrosothiols were quantified in patients with HFpEF. Parallel studies using rodent models of cardiometabolic HFpEF were performed to evaluate cardiac function, NO signaling, and total nitroso species during disease progression. Single-nucleus RNA Sequencing and proteomic analysis were conducted to identify regulatory genes and cellular targets of pathological s-nitrosylation.

Results: In patients with HFpEF, circulating nitrosothiols were significantly elevated, indicating heightened nitrosative stress, whereas nitrite levels remained unchanged. In ZSF1 Obese (ob) rats, NO bioavailability declined with age, whereas total nitroso species progressively increased as HFpEF worsened. Transcriptomic analysis revealed marked upregulation of a transnitrosylase HBb (hemoglobin-β subunit), validated in both rat and human HFpEF hearts. Enzymatic assays demonstrated aberrant functions of Trx2 (thioredoxin 2) and GSNOR (S-nitrosoglutathione reductase) in ZSF1 Ob hearts. Cell-based experiments confirmed that altered expression or function of HBb, Trx2, and GSNOR resulted in elevated cellular RxNO. Additionally, similar dysregulation of s-nitrosylation dynamics was observed in the peripheral organs, such as the kidneys and liver, in HFpEF.

Conclusions: These data demonstrate that nitrosative stress, evidenced by dysregulated protein s-nitrosylation occurs in the heart and peripheral organs in cardiometabolic HFpEF. Pathological alterations in NO bioavailability resulting from alterations in NOS expression or function alone do not account for this phenotype. Instead, pathological protein s-nitrosylation results in part from the imbalance between transnitrosylase and denitrosylase function. Restoration of physiological levels of protein s-nitrosylation and NO signaling may represent an effective therapeutic target for HFpEF.

Keywords

beta-globins; heart failure; heart failure, diastolic; hemoglobins; nitric oxide; nitrosative stress; protein processing, post-translational.

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