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Reversal of experimental pulmonary hypertension by PDGF inhibition
Ralph Theo Schermuly1, Eva Dony, Hossein Ardeschir Ghofrani
1Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany. ralph.schermuly@innere.med.uni-giessen.de
Abstract:
Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.
Insights
The PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary hypertension in animal models. This drug improved survival and reversed vascular remodeling, offering a novel therapeutic approach for severe pulmonary hypertension.
Area of Science:
- Cardiovascular Research
- Pulmonary Medicine
- Pharmacology
Background:
- Pulmonary hypertension progression involves increased pulmonary vascular smooth muscle cell proliferation and migration.
- Platelet-derived growth factor (PDGF) acts as a potent mitogen in this process.
Purpose of the Study:
- To investigate the efficacy of the PDGF receptor antagonist STI571 (imatinib) in reversing established pulmonary hypertension.
- To evaluate STI571's impact on vascular remodeling and right heart hypertrophy in experimental models.
Main Methods:
- Administered STI571 to rats with monocrotaline-induced pulmonary hypertension and chronically hypoxic mice after disease establishment.
- Monitored survival rates, right ventricular (RV) pressure via telemetry, and right heart hypertrophy.
- Assessed PDGF receptor phosphorylation and downstream signaling pathway activation.
- Examined PDGF receptor expression in human pulmonary arterial hypertension lung tissue.
Main Results:
- STI571 treatment led to 100% survival in monocrotaline-induced pulmonary hypertension rats versus 50% in controls.
- RV pressure and right heart hypertrophy were reversed to near-normal levels.
- STI571 inhibited PDGF receptor phosphorylation and downstream signaling.
- Similar therapeutic effects were observed in chronically hypoxic mice.
- Increased PDGF receptor expression was noted in human pulmonary arterial hypertension lung tissue.
Conclusions:
- STI571 effectively reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension, irrespective of the initial cause.
- STI571 represents a novel anti-remodeling therapeutic strategy for advanced pulmonary hypertension.
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