Glyoxylase-1 combats dicarbonyl stress and right ventricular dysfunction in rodent pulmonary arterial hypertension

Sasha Z Prisco, Lynn Hartweck, Jennifer L. Keen, Neal Vogel, Felipe Kazmirczak, Megan Eklund, Anna R. Hemnes, Evan L. Brittain, Kurt W. Prins

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: Heightened glycolytic flux is associated with right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH). Methylglyoxal, a glycolysis byproduct, is a highly reactive dicarbonyl that has toxic effects via non-enzymatic post-translational modifications (protein glycation). Methylglyoxal is degraded by the glyoxylase system, which includes the rate-limiting enzyme glyoxylase-1 (GLO1), to combat dicarbonyl stress. However, the potential consequences of excess protein glycation on RV function are unknown. Methods: Bioinformatics analysis of previously identified glycated proteins predicted how protein glycation regulated cardiac biology. Methylglyoxal treatment of H9c2 cardiomyocytes evaluated the consequences of excess protein glycation on mitochondrial respiration. The effects of adeno-associated virus serotype 9-mediated (AAV9) GLO1 expression on RV function in monocrotaline rats were quantified with echocardiography and hemodynamic studies. Immunoblots and immunofluorescence were implemented to probe the effects of AAV-Glo1 on total protein glycation and fatty acid oxidation (FAO) and fatty acid binding protein levels. Results: In silico analyses highlighted multiple mitochondrial metabolic pathways may be affected by protein glycation. Exogenous methylglyoxal minimally altered mitochondrial respiration when cells metabolized glucose, however methylglyoxal depressed FAO. AAV9-Glo1 increased RV cardiomyocyte GLO1 expression, reduced total protein glycation, partially restored mitochondrial density, and decreased lipid accumulation. In addition, AAV9-Glo1 increased RV levels of FABP4, a fatty acid binding protein, and hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunits alpha and beta (HADHA and HADHB), the two subunits of the mitochondrial trifunctional protein for FAO. Finally, AAV9-Glo1 blunted RV fibrosis and improved RV systolic and diastolic function. Conclusion: Excess protein glycation promotes RV dysfunction in preclinical PAH, potentially through suppression of FAO.

Original languageEnglish (US)
Article number940932
JournalFrontiers in Cardiovascular Medicine
StatePublished - Aug 25 2022

Bibliographical note

Funding Information:
KP received modest consultation fees from Actelion and Edwards and grant funding from United Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Information:
SP was funded by NIH T32 HL144472 and F32 HL154533, The University of Minnesota Clinical and Translational Science award (NIH UL1 TR002494), and the University of Minnesota Medical School Academic Investment Educational Program grant. EB was funded by NIH R01s DK124845 and HL146588. KP was funded by NIH K08 HL140100, NIH R01s HL158795, and 162927, an Innovation Grant from the American Lung Association (IA-816386), and the Cardiovascular Medical Research and Education Fund.

Publisher Copyright:
Copyright © 2022 Prisco, Hartweck, Keen, Vogel, Kazmirczak, Eklund, Hemnes, Brittain and Prins.


  • fatty acid oxidation
  • gene therapy
  • metabolism
  • mitochondria
  • right ventricular dysfunction

PubMed: MeSH publication types

  • Journal Article


Dive into the research topics of 'Glyoxylase-1 combats dicarbonyl stress and right ventricular dysfunction in rodent pulmonary arterial hypertension'. Together they form a unique fingerprint.

Cite this