J Korean Soc Hypertens.  2011 Jun;17(2):48-56. 10.5646/jksh.2011.17.2.48.

Imatinib Mesylate Attenuates Cardiac Fibrosis in Spontaneously Hypertensive Rats

• Choo EH
• Ihm SH
• Kim OR
• Jang SW
• Park CS
• Kim HY
• Chang K
• Youn HJ
• Chung WS
• Seung KB
• Kim JH

• KMID: 2196454
• DOI: http://doi.org/10.5646/jksh.2011.17.2.48

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 beta-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.

Keyword

Rats, Inbred SHR; Imatinib, Fibrosis; Echocardiography; Diastole

MeSH Terms

Animals
Benzamides
Blood Pressure
Collagen
Diastole
Echocardiography
Echocardiography, Doppler
Fibroblasts
Fibrosis
Heart
Heart Diseases
Hemodynamics
Humans
Immunoblotting
Leukemia
Male
Mesylates
Phosphorylation
Phosphotransferases
Piperazines
Platelet-Derived Growth Factor
Protein-Tyrosine Kinases
Pyrimidines
Rats
Rats, Inbred SHR
RNA, Messenger
Tyrosine
Imatinib Mesylate
Benzamides
Collagen
Mesylates
Phosphotransferases
Piperazines
Platelet-Derived Growth Factor
Protein-Tyrosine Kinases
Pyrimidines
RNA, Messenger
Tyrosine

Figure

• 

  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.

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