Increased MAO-A Activity Promotes Progression of Pulmonary Arterial Hypertension

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DOI

  • Xiao-Qing Sun, Amsterdam UMC - University of Amsterdam
  • ,
  • Eva L Peters, Free University, Amsterdam, Amsterdam UMC - University of Amsterdam
  • ,
  • Ingrid Schalij, Amsterdam UMC - University of Amsterdam
  • ,
  • Julie Birkmose Axelsen
  • Stine Andersen
  • Kondababu Kurakula
  • ,
  • Maria Catalina Gomez-Puerto, Leiden University Medical Center
  • ,
  • Robert Szulcek, Amsterdam UMC - University of Amsterdam
  • ,
  • Xiaoke Pan, Amsterdam UMC - University of Amsterdam
  • ,
  • Denielli da Silva Goncalves Bos, Amsterdam UMC - University of Amsterdam
  • ,
  • Roy Ej Schiepers, Amsterdam UMC
  • ,
  • Asger Andersen
  • Marie-José Goumans
  • ,
  • Anton Vonk Noordegraaf, Amsterdam UMC - University of Amsterdam
  • ,
  • Willem J van der Laarse, Free University Amsterdam
  • ,
  • Frances S de Man, Amsterdam UMC
  • ,
  • Harm Jan Bogaard, Amsterdam UMC

Monoamine oxidases (MAO), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A level in PAH patient lung and RV samples was compared to non-PAH donors. Experimental PAH was induced in male Sprague-Dawley rats by Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by pulmonary trunk banding (PTB). Animals were randomized to receive either saline or MAO-A inhibitor clorgyline 10 mg/kg. Echocardiography and RV catheterization was performed, heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of PAH patients and in experimental PH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodelling in SuHx rats, through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness, relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct effect on the RV. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Original languageEnglish
JournalAmerican Journal of Respiratory Cell and Molecular Biology (Online)
Volume64
Issue3
Pages (from-to)331-343
Number of pages13
ISSN1535-4989
DOIs
Publication statusPublished - Mar 2021

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