title: Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Eva Amalie
authors.initials: EA
authors.lastname: Nielsen
authors.affiliation: Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Cardiovascular Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Osami
authors.initials: O
authors.lastname: Honjo
authors.affiliation: Department of Cardiothoracic and Vascular Surgery & Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Vibeke E
authors.initials: VE
authors.lastname: Hjortdal
authors.affiliation: Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Redington
authors.affiliation: Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Friedberg
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004452:Echocardiography; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D017466:Receptors, Endothelin / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism; D018497:Ventricular Dysfunction, Right; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D011743:Pyrimidines; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C533860:macitentan