Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload.

Autor: Nielsen EA; Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Cardiothoracic and Vascular Surgery & Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark., Sun M; Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada., Honjo O; Department of Cardiovascular Surgery, Hospital for Sick Children, Toronto, Ontario, Canada., Hjortdal VE; Department of Cardiothoracic and Vascular Surgery & Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark., Redington AN; Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada., Friedberg MK; Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2016 Jan 14; Vol. 11 (1), pp. e0146767. Date of Electronic Publication: 2016 Jan 14 (Print Publication: 2016).
DOI: 10.1371/journal.pone.0146767
Abstrakt: Background: Pulmonary arterial hypertension is usually fatal due to right ventricular failure and is frequently associated with co-existing left ventricular dysfunction. Endothelin-1 is a powerful pro-fibrotic mediator and vasoconstrictor that is elevated in pulmonary arterial hypertension. Endothelin receptor blockers are commonly used as pulmonary vasodilators, however their effect on biventricular injury, remodeling and function, despite elevated isolated right ventricular afterload is unknown.
Methods: Elevated right ventricular afterload was induced by progressive pulmonary artery banding. Seven rabbits underwent pulmonary artery banding without macitentan; 13 received pulmonary artery banding + macitentan; and 5 did not undergo inflation of the pulmonary artery band (sham-operated controls).
Results: Right and left ventricular collagen content was increased with pulmonary artery banding compared to sham-operated controls and ameliorated by macitentan. Right ventricular fibrosis signaling (connective tissue growth factor and endothelin-1 protein levels); extra-cellular matrix remodeling (matrix-metalloproteinases 2 and 9), apoptosis and apoptosis-related peptides (caspases 3 and 8) were increased with pulmonary artery banding compared with sham-operated controls and decreased with macitentan.
Conclusion: Isolated right ventricular afterload causes biventricular fibrosis, right ventricular apoptosis and extra cellular matrix remodeling, mediated by up-regulation of endothelin-1 and connective tissue growth factor signaling. These pathological changes are ameliorated by dual endothelin receptor blockade despite persistent elevated right ventricular afterload.
Databáze: MEDLINE
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