Imatinib attenuates diabetes-associated atherosclerosis.
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.


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.


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.
Lassila
Markus
M
Danielle Alberti Memorial Centre for Diabetes Complications, Vascular Division, Wynn Domain, Baker Heart Research Institute, Melbourne, Victoria, Australia.
Allen
Terri J
TJ
Cao
Zemin
Z
Thallas
Vicki
V
Jandeleit-Dahm
Karin A
KA
Candido
Riccardo
R
Cooper
Mark E
ME
D000818:Animals; D001011:Aorta / Q000473:pathology; D001018:Aortic Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001549:Benzamides; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016313:Genes, abl; D020571:Genes, sis; D006442:Glycated Hemoglobin / Q000032:analysis; D000068877:Imatinib Mesylate; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin; D013599:Systole / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D001057:Apolipoproteins E; D001549:Benzamides; D016207:Cytokines; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D000068877:Imatinib Mesylate; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids; D009942:Organometallic Compounds; D010455:Peptides; D010879:Piperazines; D016315:Proto-Oncogene Proteins c-abl; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D020797:Receptor, Platelet-Derived Growth Factor beta; D013311:Streptozocin; D019010:Vascular Cell Adhesion Molecule-1; C074094:PC 1038