Disconnect between Fibrotic Response and Right Ventricular Dysfunction.

Autor:	Crnkovic S; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Egemnazarov B; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Damico R; 2 Division of Pulmonary and Critical Care Medicine and., Marsh LM; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Nagy BM; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Douschan P; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; 3 Division of Pulmonology., Atsina K; 4 Division of Cardiology, University of California, Davis, Davis, California., Kolb TM; 2 Division of Pulmonary and Critical Care Medicine and., Mathai SC; 2 Division of Pulmonary and Critical Care Medicine and., Hooper JE; 5 Department of Pathology, Johns Hopkins, Baltimore, Maryland., Ghanim B; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; 6 Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; and., Klepetko W; 6 Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; and., Fruhwald F; 7 Division of Cardiology, and., Lassner D; 8 Institute for Cardiac Diagnostic and Therapy, Berlin, Germany., Olschewski A; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Olschewski H; 3 Division of Pulmonology., Hassoun PM; 2 Division of Pulmonary and Critical Care Medicine and., Kwapiszewska G; 1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; 9 Otto Loewi Center, Physiology, Medical University of Graz, Graz, Austria.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2019 Jun 15; Vol. 199 (12), pp. 1550-1560.
DOI:	10.1164/rccm.201809-1737OC
Abstrakt:	Rationale: 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.
Databáze:	MEDLINE
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