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

• Published in: The Journal of heart and lung transplantation Vol. 30; no. 7; pp. 827 - 833
• Main Authors: Choudhary, Gaurav, MD, Troncales, Frederick, MD, Martin, Douglas, MD, Harrington, Elizabeth O., PhD, Klinger, James R., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.2011; Elsevier
• Subjects: Animals; Antihypertensive Agents - pharmacology; Biological and medical sciences; Cardiology. Vascular system; chronic hypoxia; Collagen - metabolism; Disease Models, Animal; endothelin; Endothelin Receptor Antagonists; endothelin receptor blocker; Endothelin-1 - metabolism; Fibrosis; Hypertension, Pulmonary - metabolism; Hypertrophy, Right Ventricular - etiology; Hypertrophy, Right Ventricular - prevention & control; Hypoxia - metabolism; Male; Medical sciences; Myocardium - metabolism; Myocardium - pathology; Pneumology; Protein Isoforms - metabolism; protein kinase C; Protein Kinase C - metabolism; pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Sprague-Dawley; right ventricle; Signal Transduction; Sulfonamides - pharmacology; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Ventricular Dysfunction, Right - complications; endothelin; chronic hypoxia; right ventricle; endothelin receptor blocker; pulmonary hypertension; protein kinase C; Oxygen; Respiratory disease; Right ventricle; Cardiovascular disease; Phlebology; Pulmonary hypertension; Bosentan; Fibrosis; Peptidergic receptor; Hypoxia; Models; Antagonist; Circulatory system; Cardiology; Endothelin receptor; Hypertrophy
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2011.03.010

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 (FIO2 = 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.