Imatinib Mesylate Attenuates Cardiac Fibrosis in Spontaneously Hypertensive Rats

Eun Ho Choo; Sang-Hyun Ihm; Ok-Ran Kim; Sung-Won Jang; Chan-Seok Park; Hee-Yeol Kim; Kiyuk Chang; Ho-Joong Youn; Wook Sung Chung; Ki-Bae Seung; Jae-Hyeong Kim

doi:10.5646/jksh.2011.17.2.48

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Choo, Ihm, Kim, Jang, Park, Kim, Chang, Youn, Chung, Seung, and Kim: Imatinib Mesylate Attenuates Cardiac Fibrosis in Spontaneously Hypertensive Rats

Original Article

J Korean Soc Hypertens 2011;17(2):48-56.

Published online: 10 June 2011

DOI: https://doi.org/10.5646/jksh.2011.17.2.48

Imatinib Mesylate Attenuates Cardiac Fibrosis in Spontaneously Hypertensive Rats

Eun Ho Choo, MD, Sang-Hyun Ihm, MD, Ok-Ran Kim, MS, Sung-Won Jang, MD, Chan-Seok Park, MD, Hee-Yeol Kim, MD, Kiyuk Chang, MD, Ho-Joong Youn, MD, Wook Sung Chung, MD, Ki-Bae Seung, MD, Jae-Hyeong Kim, MD

Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea

Tel: 032) 340-7027, Fax: 032) 340-2669 E-mail: limsh@catholic.ac.kr

Received 12 June 201122 June 2011 Accepted 27 June 2011

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background:

Hypertensive myocardial fibrosis promotes abnormalities of cardiac function that may adversely affect the clinical outcome of hypertensive patients. Imatinib mesylate blocks receptor tyrosine kinase and is clinically used to treat leukemia. Platelet-derived growth factor (PDGF) is a downstream target of receptor tyrosine kinases. Cardiac fibroblasts can be activated by PDGF. Thus we evaluated whether imatinib attenuate myocardial fibrosis and prevents diastolic dysfunction in spontaneously hypertensive rats (SHR).

Methods:

8 weeks old male SHRs were subjected to treatment with 8 weeks of low dose imatinib (SHR-10; 10 mg/kg), high dose imatinib (SHR-30; 30 mg/kg) or saline (SHR-C; n = 6 in each group). At the age of 16 weeks, all rats underwent hemodynamic studies and Doppler echocardiography, and were sacrificed. Their hearts were extracted for histopathological, immunoblotting and quantitative reverse transcriptase-polymerase chain reaction analyses.

Results:

While imatinib did not affect blood pressure (BP), it markedly reduced perivascular and interstitial fibrosis in the hearts of SHR. Echocardigram showed that high-dose imatinib significantly reduced left ventricular (LV) wall thickness (septal/posterior wall; SHR-C vs. SHR-30: 18 ± 2/19 ± 2 mm vs. 15 ± 1/14 ± 1 mm; p < 0.05) and improved the parameters of LV diastolic function such as E/A ratio (SHR-C vs. SHR-30: 1.60 ± 0.10 vs. 1.86 ± 0.20; p < 0.05). Imatinib also significantly reduced mRNA expression of collagen III and PDGF β-receptor tyrosine phosphorylation in the hearts of SHR.

Conclusions:

These results suggest that imatinib, especially high dose, could attenuate myocardial fibrosis and prevent LV diastolic dysfunction in hypertensive rat model by decreased activity of PDGF. Imatinib may provide a potential therapeutic approach for hypertensive heart disease.

Keywords: Rats, Inbred SHR, Imatinib, Fibrosis, Echocardiography, Diastole

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Fig. 1.

Light micrographs of the myocardium (×100, picrosirius red stain) reveal that the fibrosis of perivascular area and interstitial area is increased in SHR compared to WKY. The fibrosis of both areas was decreased after imatinib treatment in SHR (A, B). interstitial and perivascular area of WKY. (C, D). interstitial and perivascular area of SHR-control. (E, F). interstitial and perivascular area of SHR 10-mg. (G, H). interstitial and perivascular area of SHR 30-mg. WKY, Wistar Kyoto rats; SHR-control, spontaneously hypertensive rats treated with normal saline; SHR-10 mg, spontaneously hypertensive rats treated with 10 mg/kg of imatinib; SHR-30 mg, spontaneously hypertensive rats treated with 30 mg/kg of imatinib.

Fig. 2.

Collagen volume fraction of Left ventricle shows that the fibrosis of perivascular area and interstitial area is increased in SHR compared to WKY. Treatment with 30 mg/kg of imatinib in SHR significantly reduced the fibrosis of perivascular area and interstitial area. (A) Interstitial area. (B) Perivascular area. WKY, Wistar Kyoto rats; SHR-control, spontaneously hypertensive rats treated with normal saline; SHR-10 mg, spontaneously hypertensive rats treated with 10 mg/kg of imatinib; SHR-30 mg, spontaneously hypertensive rats treated with 30 mg/kg of imatinib. *p<0.05 vs. WKY. ^†p<0.05 vs. SHR.

Fig. 3.

Myocardial expression of mRNA of collagen type III was increased in SHR compared to WKY. Expression of collagen type III was significantly decreased after treatment with 30 mg/kg of imatinib. Normalization relative GAPDH was performed. (A) Electrophoresis. (B) Expression of collagen type III. GAPDH, glyceride 3-phosphate dohydroqenase; WKY, Wistar Kyoto rats; SHR-control, spontaneously hypertensive rats treated with normal saline; SHR-10 mg, spontaneously hypertensive rats treated with 10 mg/kg of imatinib; SHR-30 mg, spontaneously hypertensive rats treated with 30 mg/kg of imatinib. *p<0.05 vs. WKY. ^†p<0.05 vs. SHR.

Fig. 4.

The effect of imatinib treatment on tyrosine phosphorylation level of platelet derived growth factor (PDGF)β . Tyrosine phosphorylation level of PDFGRβ was increased in SHR compared to WKY. Treatment with 30 mg/kg of imatinib decreased the tyrosine phosphorylation level of PDFGRβ . WKY, Wistar Kyoto rats; SHR-control, spontaneously hypertensive rats treated with normal saline; SHR-10 mg, spontaneously hypertensive rats treated with 10 mg/kg of imatinib; SHR-30 mg, spontaneously hypertensive rats treated with 30 mg/kg of imatinib.*p<0.05 vs. WKY. ^†p<0.05 vs. SHR.

Table 1.

General characteristics

	WKY	SHR	SHR-10 mg	SHR-30 mg
Pre-BWt (g)	206 ±10	184 ±11^*	187 ±6^*	183 ±13^*
Post-BWt (g)	390 ±12	346 ±8^*	334 ±24^*	339 ±16^*
Systolic BP (mm Hg)	114 ±8	166 ±14^*	163 ±8^*	170 ±13^*
Heart weight (g)	1.2 ±0.1	1.5 ±0.1^*	1.3 ±0.1	1.4 ±0.1^*
Tibia length (mm)	5.2 ±0.4	4.8 ±0.2	4.8 ±0.3	4.8 ±0.2
Heart/Tibia ratio (g/mm)	0.23 ±0.01	0.31 ±0.03^*	0.28 ±0.02^*	0.30 ±0.02^*

Data are expressed as mean±standard deviation.

WKY, Wista Kyoto rat; SHR, spontaneous hypertensive rat; SHR-10 mg, SHR treated with 10 mg/kg of imatinib; SHR-30 mg, SHR treated with 30 mg/kg of imatinib; Pre-BWt, body weight before treatment; Post-BWt. body weight after treatment; BP, blood pressure.

^* p<0.05 vs. WKY.

^† p<0.05 vs. SHR.

Table 2.

Echocardiographic parameters

	WKY	SHR	SHR-10 mg	SHR-30 mg
IVS (cm)	0.12 ± 0.01	0.18 ± 0.02^*	0.17 ± 0.02^*	0.15 ± 0.01^*††
PW (cm)	0.12 ± 0.01	0.19 ± 0.02^*	0.17 ± 0.02^*	0.14 ± 0.01^††
LVEDD (cm)	0.64 ± 0.04	0.67 ± 0.04	0.66 ± 0.08	0.59 ± 0.10
LVESD (cm)	0.34 ± 0.02	0.40 ± 0.02^*	0.35 ± 0.06	0.33 ± 0.03
FS (%)	47 ± 2	44 ± 2	47 ± 3	47 ± 3
E (m/sec)	1.27 ± 0.08	1.08 ± 0.21	1.04 ± 0.23	1.09 ± 0.09
A (m/sec)	0.64 ± 0.06	0.68 ± 0.16	0.60 ± 0.16	0.59 ± 0.08
HR (beat/min)	313 ± 11	305 ± 12	307 ± 14	302 ± 8
E/A	1.97 ± 0.07	1.60 ± 0.10^*	1.78 ± 0.10	1.86 ± 0.20^††
DT (msec)	29.7 ± 3.3	38.8 ± 2.2^*	35.8 ± 3.5^*	34 ± 3.7^††

Data are expressed as mean±standard deviation.

WKY, Wista Kyoto rat; SHR, spontaneous hypertensive rat; SHR-10 mg, SHR treated with 10 mg/kg of imatinib; SHR-30 mg, SHR treated with 30 mg/kg of imatinib; IVS, interventricular septal thickness; PW, posterior wall thickness; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; FS, fractional shortening of LV diameter; E, peak velocity of early transmitral inflow; A, peak velocity of late transmitral inflow; HR, heart rat; DT, deceleration time.

^* p<0.05 vs. WKY.

^† p<0.05 vs. SHR.

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