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

ABSTRACT: 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.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.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-? protein expression, but had no effect on PKC-? or -? isoforms. Administration with bosentan did not affect total PKC-? protein expression. However, animals treated with bosentan had an increase in membranous PKC-? when exposed to hypoxia.Bosentan inhibits RVH and RV collagen expression in rats exposed to chronic hypoxia, possibly via alteration of PKC-? activity.

SUBMITTER: Choudhary G

PROVIDER: S-EPMC3536478 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Choudhary Gaurav G Troncales Frederick F Martin Douglas D Harrington Elizabeth O EO Klinger James R JR

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20110508 7

<h4>Background</h4>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.<h4>Methods</h4>Adult Sprague-Dawley rats were housed ...[more]

PMID: 21550822

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Project description:Echocardiography is the gold standard non-invasive technique to diagnose pulmonary hypertension. It is also an important modality used to monitor disease progression and response to treatment in patients with pulmonary hypertension. Surprisingly, only few studies have been conducted to validate and standardize echocardiographic parameters in experimental animal models of pulmonary hypertension. We sought to define cut-off values for both invasive and non-invasive measures of pulmonary hemodynamics and right ventricular hypertrophy that would reliably diagnose pulmonary hypertension in three different rat models. The study was designed in two phases: (1) a derivation phase to establish the cut-off values for invasive measures of right ventricular systolic pressure, Fulton's index (right ventricular weight/left ventricle?+?septum weight), right ventricular to body weight ratio, and non-invasive echocardiographic measures of pulmonary arterial acceleration time, pulmonary arterial acceleration time to ejection time ratio and right ventricular wall thickness in diastole in the hypoxic and monocrotaline rat models of pulmonary hypertension and (2) a validation phase to test the performance of the cut-off values in predicting pulmonary hypertension in an independent cohort of rats with Sugen/hypoxia-induced pulmonary hypertension. Our study demonstrates that right ventricular systolic pressure ?35.5?mmHg and Fulton's Index ?0.34 are highly sensitive (>94%) and specific (>91%) cut-offs to distinguish animals with pulmonary hypertension from controls. When pulmonary arterial acceleration time/ejection time and right ventricular wall thickness in diastole were both measured, a result of either pulmonary arterial acceleration time/ejection time ?0.25 or right ventricular wall thickness in diastole ?1.03?mm detected right ventricular systolic pressure ?35.5?mmHg or Fulton's Index ?0.34 with a sensitivity of 88% and specificity of 100%. With properly validated non-invasive echocardiography measures of right ventricular performance in rats that accurately predict invasive measures of pulmonary hemodynamics, future studies can now utilize these markers to test the efficacy of different treatments with preclinical therapeutic modeling.

Dataset Information

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

Publications

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

Similar Datasets

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