Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension.

Abstract

BACKGROUND:

Maladaptive right ventricular (RV) hypertrophic responses lead to RV dysfunction and failure in patients with pulmonary arterial hypertension, but the mechanisms responsible for these changes are not well understood. The objective of this study was to evaluate the effect of treatment with bosentan on RV hypertrophy (RVH), fibrosis and expression of protein kinase C (PKC) isoforms in the RV of rats exposed to chronic hypoxia.

METHODS:

Adult Sprague-Dawley rats were housed in normoxia or hypoxia (FIO(2) = 10%) and administered vehicle or 100 mg/kg/day bosentan. After 3 weeks, echocardiographic and hemodynamic assessment was performed. PKC, procollagen-1 and collagen expression levels were assessed using immunoblot or colorimetric assay.

RESULTS:

RV systolic pressure (RVSP) and RVH were higher in hypoxic compared with normoxic animals (RVSP: 72 ± 4 vs 25 ± 2 mm Hg, p < 0.05; RVH: 1.2 ± 0.06 vs 0.5 ± 0.03 mg/g body weight, p < 0.05). Bosentan had no effect on RVSP or mass in normoxic animals, but did attenuate RVH in hypoxic animals (hypoxic/vehicle: 1.2 ± 0.06; hypoxic/bosentan: 1.0 ± 0.05 mg/g body weight; p < 0.05). Hypoxia increased RV procollagen-1, and total collagen expression, effects that were attenuated by bosentan treatment. Hypoxia increased RV total and cytosolic PKC-δ protein expression, but had no effect on PKC-α or -ε isoforms. Administration with bosentan did not affect total PKC-δ protein expression. However, animals treated with bosentan had an increase in membranous PKC-δ when exposed to hypoxia.

CONCLUSIONS:

Bosentan inhibits RVH and RV collagen expression in rats exposed to chronic hypoxia, possibly via alteration of PKC-δ activity.

• Authors: Gaurav Choudhary, Frederick Troncales, Douglas Martin, Elizabeth O Harrington, James R Klinger
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 30 Issue 7 Pg. 827-33 (Jul 2011) ISSN: 1557-3117 [Electronic] United States
• PMID: 21550822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Inc.

Chemical References

• Antihypertensive Agents
• Endothelin Receptor Antagonists
• Endothelin-1
• Protein Isoforms
• Sulfonamides
• Collagen
• Protein Kinase C
• Bosentan

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Bosentan
• Collagen (metabolism)
• Disease Models, Animal
• Endothelin Receptor Antagonists
• Endothelin-1 (metabolism)
• Fibrosis
• Hypertension, Pulmonary (metabolism)
• Hypertrophy, Right Ventricular (etiology, prevention & control)
• Hypoxia (metabolism)
• Male
• Myocardium (metabolism, pathology)
• Protein Isoforms (metabolism)
• Protein Kinase C (metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Sulfonamides (pharmacology)
• Ventricular Dysfunction, Right (complications)