Imatinib Mesylate Attenuates Myocardial Remodeling Through Inhibition of Platelet-Derived Growth Factor and Transforming Growth Factor Activation in a.

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Imatinib Mesylate Attenuates Myocardial Remodeling Through Inhibition of Platelet-Derived Growth Factor and Transforming Growth Factor Activation in a Rat Model of HypertensionNovelty and Significance by Sung-Won Jang, Sang-Hyun Ihm, Eun-Ho Choo, Ok-Ran Kim, Kiyuk Chang, Chan-Seok Park, Hee-Yeol Kim, and Ki-Bae Seung Hypertension Volume 63(6):1228-1234 May 7, 2014 Copyright © American Heart Association, Inc. All rights reserved.

Comparison of left ventricular wall thickness and mitral inflow pattern. Comparison of left ventricular wall thickness and mitral inflow pattern. M-mode echocardiography demonstrated that left ventricular wall is thicker in spontaneously hypertensive rats treated with placebo (SHR-C) than that in Wistar–Kyoto (WKY). Treatment with imatinib prevented left ventricular hypertrophy (A). Doppler echocardiography displayed that early to late diastolic peak velocity (E/A) ratio was reduced in SHR when compared with that in WKY, and this was reversed with imatinib treatment (B). SHR-I indicates spontaneously hypertensive rats treated with imatinib. Sung-Won Jang et al. Hypertension. 2014;63:1228-1234 Copyright © American Heart Association, Inc. All rights reserved.

Fibrosis of interstitial and perivascular areas was increased in spontaneously hypertensive rat (SHR) when compared with that in Wistar–Kyoto (WKY). Fibrosis of interstitial and perivascular areas was increased in spontaneously hypertensive rat (SHR) when compared with that in Wistar–Kyoto (WKY). Treatment with 30 mg/kg per d of imatinib in SHR significantly reduced the fibrosis of interstitial (A) and perivascular areas (C). Quantitative measurement using collagen area fraction shows that imatinib significantly decreased the amount of fibrosis in interstitial areas (B) and perivascular areas (D). Results are shown as mean±SD of 8 different rats. *P<0.05 vs WKY; †P<0.05 vs SHR-C. LV indicates left ventricular; and SHR-I, spontaneously hypertensive rats treated with imatinib. Sung-Won Jang et al. Hypertension. 2014;63:1228-1234 Copyright © American Heart Association, Inc. All rights reserved.

Myocardial mRNA expression of collagen type I and III was increased in spontaneously hypertensive rat (SHR) when compared with that in Wistar–Kyoto (WKY). Myocardial mRNA expression of collagen type I and III was increased in spontaneously hypertensive rat (SHR) when compared with that in Wistar–Kyoto (WKY). Expression of collagen type I and III was significantly decreased after treatment with 30 mg/kg day of imatinib. The mRNA expression of transforming growth factor (TGF)-β1 was also increased in SHR, which was attenuated with imatinib treatment. Normalization relative to GAPDH was performed. Electrophoresis (A), mRNA expression of collagen type I (B), type III (C), mRNA expression of TGF-β1 (D). Results are shown as mean±SD of 8 different rats. *P<0.05 vs WKY; †P<0.05 vs SHR-C. SHR-C indicates spontaneously hypertensive rats treated with placebo; and SHR-I, spontaneously hypertensive rats treated with imatinib. Sung-Won Jang et al. Hypertension. 2014;63:1228-1234 Copyright © American Heart Association, Inc. All rights reserved.

Effect of imatinib treatment on the tyrosine phosphorylation and total protein level of platelet-derived growth factor receptor (PDGFR)-β. Effect of imatinib treatment on the tyrosine phosphorylation and total protein level of platelet-derived growth factor receptor (PDGFR)-β. A, Tyrosine phosphorylation and total protein level of PDFGR-β was increased in spontaneously hypertensive rat (SHR) when compared with Wistar–Kyoto (WKY). Treatment with 30 mg/kg per day of imatinib decreased the tyrosine phosphorylation (B) and total protein level of PDFGR-β (C). Results are shown as mean±SD of 8 different rats. *P<0.05 vs WKY; †P<0.05 vs SHR-C. SHR-C indicates spontaneously hypertensive rats treated with placebo; and SHR-I, spontaneously hypertensive rats treated with imatinib. Sung-Won Jang et al. Hypertension. 2014;63:1228-1234 Copyright © American Heart Association, Inc. All rights reserved.

Effect of imatinib on platelet-derived growth factor receptor (PDGFR)-β phosphorylation in PDGF-BB–treated rat cardiac fibroblasts. Effect of imatinib on platelet-derived growth factor receptor (PDGFR)-β phosphorylation in PDGF-BB–treated rat cardiac fibroblasts. Incubation of cultured rat cardiac fibroblasts with PDGF-BB increased the phosphorylation of PDGFR-β. Coincubation of the cells with imatinib blocked the PDGFR-β phosphorylation (A) and decreased mRNA expression of collagen type III (B). *P<0.05 vs PDGF-BB (−) and imatinib (−); †P<0.05 vs PDGF-BB (+) and imatinib (−), n=5. Sung-Won Jang et al. Hypertension. 2014;63:1228-1234 Copyright © American Heart Association, Inc. All rights reserved.

Effect of imatinib on c-Abl phosphorylation in transforming growth factor (TGF)-β1–treated rat cardiac fibroblasts. Effect of imatinib on c-Abl phosphorylation in transforming growth factor (TGF)-β1–treated rat cardiac fibroblasts. Incubation of cultured rat cardiac fibroblasts with TGF-β1 increased the phosphorylation of c-abl. Coincubation of the cells with imatinib blocked c-abl phosphorylation (A) and decreased mRNA expression of collagen type III (B). *P<0.05 vs TGF-β1 (−) and imatinib (−); †P<0.05 vs TGF-β1 (+) and imatinib (−), n=5. Sung-Won Jang et al. Hypertension. 2014;63:1228-1234 Copyright © American Heart Association, Inc. All rights reserved.