on February 26, 2004
Published online before print February 26, 2004, doi: 10.1161/01.ATV.0000124105.39900.db
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 24, 2003
Accepted on January 22, 2004
Imatinib Attenuates Diabetes-Associated Atherosclerosis
Markus Lassila ;
From Danielle Alberti Memorial Centre for Diabetes Complications, Vascular Division, Wynn Domain, Baker Heart Research Institute, Melbourne, Victoria, Australia.
* To whom correspondence should be addressed. E-mail: mark.cooper{at}baker.edu.au.
Objective--Diabetes is associated with accelerated atherosclerosis, the major factor contributing to increased mortality and morbidity in this 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.
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 
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.
Key words: atherosclerosis • diabetes mellitus • apolipoprotein E knockout mice • platelet-derived growth factor • vasculature
This article has been cited by other articles:
 |
|
 |
|
  A. Templeton, M. Brandle, T. Cerny, and S. Gillessen Remission of diabetes while on sunitinib treatment for renal cell carcinoma Ann. Onc., April 1, 2008; 19(4): 824 - 825. [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. Schellings, B. Lowenberg, Y. M. Pinto, and K. Strebhardt Another Look at Imatinib Mesylate N. Engl. J. Med., March 15, 2007; 356(11): 1183 - 1183. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hansmann, R. A. Wagner, S. Schellong, V. A. de Jesus Perez, T. Urashima, L. Wang, A. Y. Sheikh, R. S. Suen, D. J. Stewart, and M. Rabinovitch Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor-{gamma} Activation Circulation, March 13, 2007; 115(10): 1275 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Gologan, G. Constantinescu, D. Georgescu, D. Ostroveanu, D. Vasilache, C. Dobrea, D. Iancu, and V. Popov Hypolipemiant besides Antileukemic Effect of Imatinib Mesylate (Case Report). Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 4832 - 4832. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Ushio-Fukai and R. W. Alexander Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle Hypertension, November 1, 2006; 48(5): 797 - 803. [Full Text] [PDF]
|
|
|
|
|
|
M. W.M. Schellings, M. Baumann, R. E.W. van Leeuwen, R. F.J.J. Duisters, S. H.P. Janssen, B. Schroen, C. J. Peutz-Kootstra, S. Heymans, and Y. M. Pinto Imatinib Attenuates End-Organ Damage in Hypertensive Homozygous TGR(mRen2)27 Rats Hypertension, March 1, 2006; 47(3): 467 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ushio-Fukai, L. Zuo, S. Ikeda, T. Tojo, N. A. Patrushev, and R. W. Alexander cAbl Tyrosine Kinase Mediates Reactive Oxygen Species- and Caveolin-Dependent AT1 Receptor Signaling in Vascular Smooth Muscle: Role in Vascular Hypertrophy Circ. Res., October 14, 2005; 97(8): 829 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Veneri, M. Franchini, and E. Bonora Imatinib and Regression of Type 2 Diabetes N. Engl. J. Med., March 10, 2005; 352(10): 1049 - 1050. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lassila, K. Jandeleit-Dahm, K. K. Seah, C. M. Smith, A. C. Calkin, T. J. Allen, and M. E. Cooper Imatinib Attenuates Diabetic Nephropathy in Apolipoprotein E-Knockout Mice J. Am. Soc. Nephrol., February 1, 2005; 16(2): 363 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kadowaki and N. Kubota Protective Role of Imatinib in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 801 - 803. [Full Text]
|
|