• Slaven Crnkovic, Bakytbek Egemnazarov, Rachel Damico, Leigh M Marsh, Bence M Nagy, Philipp Douschan, Kwame Atsina, Todd M Kolb, Stephen C Mathai, Jody E Hooper, Bahil Ghanim, Walter Klepetko, Friedrich Fruhwald, Dirk Lassner, Andrea Olschewski, Horst Olschewski, Paul M Hassoun, and Grazyna Kwapiszewska.
• 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
• Am. J. Respir. Crit. Care Med. 2019 Jun 15; 199 (12): 155015601550-1560.

AbstractRationale: Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension. Objectives: To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function. Methods: Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice. Measurements and Main Results: Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFRα (platelet-derived growth factor receptor-α), but generally lacked αSMA (α-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs. Conclusions: We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFRα/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.

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