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

• Published in: PloS one 2016-01, Vol.11 (1), p.e0146767-e0146767
• Main Authors: Nielsen, Eva Amalie, Sun, Mei, Honjo, Osami, Hjortdal, Vibeke E, Redington, Andrew N, Friedberg, Mark K
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Banding; Cardiology; Care and treatment; Clinical medicine; Collagen; Complications and side effects; Connective tissue growth factor; Connective tissues; Diagnosis; Disease Models, Animal; Drug dosages; Echocardiography; Endothelin 1; Endothelin-1 - blood; Endothelin-1 - metabolism; Endothelins; Experiments; Extracellular Matrix - metabolism; Fibrosis; Gene Expression; Growth factors; Heart; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Hemodynamics; Hypertension; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Laboratory animals; Male; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Medical research; Mortality; Ostomy; Peptides; Physiological aspects; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; Pyrimidines - blood; Pyrimidines - metabolism; Rabbits; Receptors, Endothelin - metabolism; Right ventricular failure; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Signaling; Sulfonamides - blood; Sulfonamides - metabolism; Vascular surgery; Vasodilators; Veins & arteries; Ventricle; Ventricular Dysfunction, Right; Ventricular Remodeling - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0146767

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. 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). 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. 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.