title: Imatinib mesylate attenuates myocardial remodeling through inhibition of platelet-derived growth factor and transforming growth factor activation in a rat model of hypertension.
abstract: Imatinib mesylate is a specific tyrosine kinase inhibitor that may block the platelet-derived growth factor and transforming growth factor pathways. These pathways are known to provoke fibroblast activation. We evaluated whether imatinib, by inhibiting these pathways, prevents diastolic dysfunction and attenuates myocardial remodeling using spontaneously hypertensive rats (SHRs). Eight-week-old male SHRs were randomly assigned to either imatinib treatment group (30 mg/kg per day; n=10; SHR-I) or hypertensive control group (distilled water, n=10; SHR-C). Wistar-Kyoto rats were used as normal controls (n=10). At 16 weeks, all rats underwent hemodynamic studies and Doppler echocardiography and then were euthanized. Their hearts were extracted for histopathologic, immunoblotting, and quantitative reverse transcriptase polymerase chain reaction analyses. Although imatinib did not affect blood pressure, it markedly reduced perivascular and interstitial fibrosis in the hearts of SHR. Echocardiogram showed that imatinib significantly reduced the left ventricular wall thickness (septal/posterior wall; SHR-C versus SHR-I, 18±1/19±2 versus 15±1/15±1 mm; P<0.001) and increased the E/A ratio (SHR-C versus SHR-I, 1.59±0.11 versus 1.84±0.16; P=0.001). Also, imatinib significantly reduced the mRNA expression of collagen type I, III, and platelet-derived growth factor receptor-β phosphorylation in the hearts of SHR. In addition, imatinib reduced collagen production by inhibiting the phosphorylation of c-abl and platelet-derived growth factor receptor-β in rat cardiac fibroblasts. In conclusion, these results suggest that imatinib could attenuate myocardial remodeling and improve left ventricular diastolic dysfunction in a hypertensive rat model by affecting platelet-derived growth factor and transforming growth factor-β1 pathway without the blood pressure-lowering effect.
authors.affiliation: Division of Cardiology, Bucheon St. Mary's Hospital, The Catholic University of Korea, 2 Sosa-Dong, Wonmi-Gu, Bucheon-City, Gyeonggi-Do 420-717 South Korea. limsh@catholic.ac.kr.
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Jang
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Ihm
authors.forename: Eun-Ho
authors.initials: EH
authors.lastname: Choo
authors.forename: Ok-Ran
authors.initials: OR
authors.lastname: Kim
authors.forename: Kiyuk
authors.initials: K
authors.lastname: Chang
authors.forename: Chan-Seok
authors.initials: CS
authors.lastname: Park
authors.forename: Hee-Yeol
authors.initials: HY
authors.lastname: Kim
authors.forename: Ki-Bae
authors.initials: KB
authors.lastname: Seung
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000068877:Imatinib Mesylate; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001549:Benzamides; D024042:Collagen Type I; D024061:Collagen Type III; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053773:Transforming Growth Factor beta1; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl
keywords: imatinib; platelet-derived growth factor; rats, inbred SHR; transforming growth factor beta; ventricular remodeling