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PMID: 16200212 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Reversal of experimental pulmonary hypertension by PDGF inhibition.

The Journal of clinical investigation ·Vol. 115 ·No. 10 ·2005-10-00 ·Pages 2811-21

Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F

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.

MeSH Terms
Animals Benzamides Blood Pressure/drug effects Disease Models, Animal Heart Ventricles/metabolism,pathology Humans Hypertension, Pulmonary/drug therapy,pathology,physiopathology Imatinib Mesylate Lung/blood supply,metabolism,pathology Male Mice Piperazines/administration & dosage Platelet-Derived Growth Factor/metabolism Protein Kinase Inhibitors/administration & dosage Pulmonary Artery/metabolism,pathology Pyrimidines/administration & dosage Rats Rats, Sprague-Dawley Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors,metabolism Signal Transduction/drug effects
Chemicals
Benzamides Piperazines Platelet-Derived Growth Factor Protein Kinase Inhibitors Pyrimidines Imatinib Mesylate Receptors, Platelet-Derived Growth Factor
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Schermuly Ralph Theo
Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany. [email protected]
Dony Eva
Ghofrani Hossein Ardeschir
Pullamsetti Soni
Savai Rajkumar
Roth Markus
Sydykov Akylbek
Lai Ying Ju
Weissmann Norbert
Seeger Werner
Grimminger Friedrich
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI24838
Email
[email protected]
Published
2005-10-00
Pages
2811-21
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1236676
Subset
IM
Corrections
CommentIn
PMID: 16200204
External Links
PubMed source DOI: 10.1172/JCI24838 PMC Full Text View journal details
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