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Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload.
PLoS One. 2016; 11(1):e0146767.Plos

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.

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.

Authors+Show Affiliations

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.Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.Department of Cardiovascular Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.Department of Cardiothoracic and Vascular Surgery & Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark.Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26765263

Citation

Nielsen, Eva Amalie, et al. "Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload." PloS One, vol. 11, no. 1, 2016, pp. e0146767.
Nielsen EA, Sun M, Honjo O, et al. Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload. PLoS ONE. 2016;11(1):e0146767.
Nielsen, E. A., Sun, M., Honjo, O., Hjortdal, V. E., Redington, A. N., & Friedberg, M. K. (2016). Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload. PloS One, 11(1), e0146767. https://doi.org/10.1371/journal.pone.0146767
Nielsen EA, et al. Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload. PLoS ONE. 2016;11(1):e0146767. PubMed PMID: 26765263.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload. AU - Nielsen,Eva Amalie, AU - Sun,Mei, AU - Honjo,Osami, AU - Hjortdal,Vibeke E, AU - Redington,Andrew N, AU - Friedberg,Mark K, Y1 - 2016/01/14/ PY - 2015/03/06/received PY - 2015/12/22/accepted PY - 2016/1/15/entrez PY - 2016/1/15/pubmed PY - 2016/7/12/medline SP - e0146767 EP - e0146767 JF - PloS one JO - PLoS ONE VL - 11 IS - 1 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26765263/Dual_Endothelin_Receptor_Blockade_Abrogates_Right_Ventricular_Remodeling_and_Biventricular_Fibrosis_in_Isolated_Elevated_Right_Ventricular_Afterload_ L2 - http://dx.plos.org/10.1371/journal.pone.0146767 DB - PRIME DP - Unbound Medicine ER -