title: Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats.
abstract: 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-beta (PDGFRbeta), 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 PDGFRbeta 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 PDGFRbeta 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 PDGFRbeta. The simultaneous improvement in both heart and kidneys suggests that inhibition of the PDGFRbeta has broad protective effects that may provide novel avenues for a blood pressure-independent protection against end-organ damage.
authors.affiliation: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, The Netherlands.
authors.forename: Mark W M
authors.initials: MW
authors.lastname: Schellings
authors.forename: Marcus
authors.initials: M
authors.lastname: Baumann
authors.forename: Rick E W
authors.initials: RE
authors.lastname: van Leeuwen
authors.forename: Rudy F J J
authors.initials: RF
authors.lastname: Duisters
authors.forename: Suzanne H P
authors.initials: SH
authors.lastname: Janssen
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz-Kootstra
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001160:Arterioles / Q000187:drug effects / Q000473:pathology; D001549:Benzamides; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D005355:Fibrosis; D006331:Heart Diseases / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D006720:Homozygote; D006973:Hypertension / Q000150:complications / Q000235:genetics*; D000068877:Imatinib Mesylate; D007668:Kidney / Q000098:blood supply; D007674:Kidney Diseases / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012083:Renin / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C473112:Ren2 protein, mouse; D000068877:Imatinib Mesylate; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D012083:Renin