This Article Full Text Full Text (PDF) All Versions of this Article: 47/3/467    most recent 01.HYP.0000202487.68969.f7v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schellings, M. W.M. Articles by Pinto, Y. M. Search for Related Content PubMed PubMed Citation Articles by Schellings, M. W.M. Articles by Pinto, Y. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Diseases High Blood Pressure Kidney Diseases Hazardous Substances DB IMATINIB MESYLATE Related Collections Cardio-renal physiology/pathophysiology Remodeling Animal models of human disease Hypertension - basic studies Related Article

(Hypertension. 2006;47:467.)
© 2006 American Heart Association, Inc.

Original Articles

Imatinib Attenuates End-Organ Damage in Hypertensive Homozygous TGR(mRen2)27 Rats

Mark W.M. Schellings; Marcus Baumann; Rick E.W. van Leeuwen; Rudy F.J.J. Duisters; Suzanne H.P. Janssen; Blanche Schroen; Carine J. Peutz-Kootstra; Stephane Heymans; Yigal M. Pinto

From Experimental and Molecular Cardiology (M.W.M.S., R.E.W.v.L., R.F.J.J.D., S.H.P.J., B.S., S.H., Y.M.P.), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Department of Pharmacology (M.B.), Maastricht University, the Netherlands; and Department of Pathology (C.J.P.-K.), University Hospital Maastricht, the Netherlands.

Correspondence to Yigal M. Pinto, MD, PhD, Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, P Debyelaan 25, 6202 AZ Maastricht, The Netherlands. E-mail y.pinto{at}cardio.azm.nl

Imatinib specifically inhibits receptor tyrosine kinase signaling and is clinically used to treat leukemia. Receptor tyrosine kinases not only mediate tumor growth but also initiate adverse signaling in heart failure. We investigated whether imatinib, by inhibiting the platelet-derived growth factor receptor-ß (PDGFRß), prevents cardiac and renal damage in TGR(mRen2)27 (Ren2) rats. Eight-week-old male homozygous Ren2 and Sprague Dawley rats were treated either with imatinib (30 mg/kg; STI-571) or placebo for 8 weeks (Ren2 n=12 for each group; Sprague Dawley n=6 for each group). Imatinib did not affect blood pressure or left ventricular (LV) hypertrophy in both groups. Imatinib attenuated the decline in fractional shortening (imatinib versus Ren2 placebo 45±4.5% versus 32±3%; n=7–11; P<0.05) and in diastolic function in Ren2 rats (baseline diastolic dP/dt corrected for systolic blood pressure Ren2 imatinib versus Ren2 placebo 38.6±0.67 versus 35.3±0.41 [1 · s^–1]; n=7–11; P<0.05). This was associated with decreased cardiac fibrosis and decreased activation of PDGFRß and extracellular signal-regulated kinase 1/2. Renal microvascular hypertrophy and perivascular fibrosis in Ren2 rats were significantly decreased by imatinib. In vitro, imatinib blocked angiotensin II-induced activation of the PDGFRß and significantly decreased fibroblast proliferation and collagen production. In conclusion, imatinib did not affect LV hypertrophy but attenuated the decline in cardiac function and reduced renal microvascular damage associated with reduced activation of the PDGFRß. The simultaneous improvement in both heart and kidneys suggests that inhibition of the PDGFRß has broad protective effects that may provide novel avenues for a blood pressure-independent protection against end-organ damage.

Key Words: platelet-derived growth factor • angiotensin II • hypertrophy • fibrosis

Related Article:

Growth Factor Receptor Transactivation in Mediating End Organ Damage by Angiotensin II

Hiroyuki Suzuki and Satoru Eguchi
Hypertension 2006 47: 339-340. [Full Text] [PDF]

This article has been cited by other articles:

				V. Gioni, T. Karampinas, G. Voutsinas, A. E. Roussidis, S. Papadopoulos, N. K. Karamanos, and D. Kletsas Imatinib Mesylate Inhibits Proliferation and Exerts an Antifibrotic Effect in Human Breast Stroma Fibroblasts Mol. Cancer Res., May 1, 2008; 6(5): 706 - 714. [Abstract] [Full Text] [PDF]

				E. Atallah, J.-B. Durand, H. Kantarjian, and J. Cortes Congestive heart failure is a rare event in patients receiving imatinib therapy Blood, August 15, 2007; 110(4): 1233 - 1237. [Abstract] [Full Text] [PDF]

				M. H. de Borst, S. H. Diks, J. Bolbrinker, M. W. Schellings, M. B. A. van Dalen, M. P. Peppelenbosch, R. Kreutz, Y. M. Pinto, G. Navis, and H. van Goor Profiling of the renal kinome: a novel tool to identify protein kinases involved in angiotensin II-dependent hypertensive renal damage Am J Physiol Renal Physiol, July 1, 2007; 293(1): F428 - F437. [Abstract] [Full Text] [PDF]

				P. Boor, A. Konieczny, L. Villa, U. Kunter, C. R.C. van Roeyen, W. J. LaRochelle, G. Smithson, S. Arrol, T. Ostendorf, and J. Floege PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1323 - 1331. [Abstract] [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]

				J.-K. Park, R. Fischer, R. Dechend, E. Shagdarsuren, A. Gapeljuk, M. Wellner, S. Meiners, P. Gratze, N. Al-Saadi, S. Feldt, et al. p38 Mitogen-Activated Protein Kinase Inhibition Ameliorates Angiotensin II-Induced Target Organ Damage Hypertension, March 1, 2007; 49(3): 481 - 489. [Abstract] [Full Text] [PDF]

				H. Suzuki and S. Eguchi Growth Factor Receptor Transactivation in Mediating End Organ Damage by Angiotensin II Hypertension, March 1, 2006; 47(3): 339 - 340. [Full Text] [PDF]