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Imatinib attenuates diabetes-associated atherosclerosis.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2004 May; Vol. 24 (5), pp. 935-42. Date of Electronic Publication: 2004 Feb 26. - Publication Year :
- 2004
-
Abstract
- Objective: Diabetes is associated with accelerated atherosclerosis, the major factor contributing to increased mortality and morbidity in the diabetic population. The molecular mechanisms by which diabetes promotes atherosclerosis are not fully understood. Platelet-derived growth factor has been shown to play a major role in the pathology of vascular diseases, but whether it plays a role in atherosclerosis associated with diabetes remains unknown. The aims of this study were to assess whether platelet-derived growth factor-dependent pathways are involved in the development of diabetes-induced atherosclerosis and to determine the effects of platelet-derived growth factor receptor antagonism on this disorder.<br />Methods and Results: Diabetes was induced by injection of streptozotocin in 6-week-old apolipoprotein E knockout mice. Diabetic animals received treatment with a tyrosine kinase inhibitor that inhibits platelet-derived growth factor action, imatinib (STI-571, 10 mg/kg per day), or no treatment for 20 weeks. Nondiabetic apolipoprotein E knockout mice served as controls. Induction of diabetes was associated with a 5-fold increase in plaque area in association with an increase in aortic platelet-derived growth factor-B expression and platelet-derived growth factor-beta receptor phosphorylation as well as other prosclerotic and proinflammatory cytokines. Imatinib treatment prevented the development of atherosclerotic lesions and diabetes-induced inflammatory cytokine overexpression in the aorta.<br />Conclusions: Tyrosine kinase inhibition with imatinib appears to be a novel therapeutic option to retard the development of atherosclerosis, specifically in the context of diabetes.
- Subjects :
- Animals
Aorta pathology
Aortic Diseases drug therapy
Aortic Diseases etiology
Aortic Diseases pathology
Apolipoproteins E deficiency
Apolipoproteins E genetics
Arteriosclerosis etiology
Arteriosclerosis pathology
Benzamides
Cytokines biosynthesis
Cytokines genetics
Diabetes Mellitus, Experimental chemically induced
Drug Evaluation, Preclinical
Enzyme Inhibitors pharmacology
Enzyme Inhibitors therapeutic use
Genes, abl
Genes, sis
Glycated Hemoglobin analysis
Imatinib Mesylate
Intercellular Signaling Peptides and Proteins
Lipids blood
Male
Mice
Mice, Knockout
Organometallic Compounds metabolism
Peptides genetics
Peptides metabolism
Piperazines pharmacology
Proto-Oncogene Proteins c-abl biosynthesis
Proto-Oncogene Proteins c-sis biosynthesis
Pyrimidines pharmacology
Random Allocation
Receptor, Platelet-Derived Growth Factor beta biosynthesis
Receptor, Platelet-Derived Growth Factor beta genetics
Reverse Transcriptase Polymerase Chain Reaction
Streptozocin
Systole drug effects
Vascular Cell Adhesion Molecule-1 biosynthesis
Vascular Cell Adhesion Molecule-1 genetics
Arteriosclerosis drug therapy
Diabetes Mellitus, Experimental complications
Diabetic Angiopathies drug therapy
Piperazines therapeutic use
Proto-Oncogene Proteins c-sis physiology
Pyrimidines therapeutic use
Receptor, Platelet-Derived Growth Factor beta antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 24
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 14988091
- Full Text :
- https://doi.org/10.1161/01.ATV.0000124105.39900.db