Abstract 12763: Imatinib Mesylate Attenuates Hypertensive Cardiovascular Remodeling in Spontaneously Hypertensive Rats
Background: Pressure overload induces cardiac fibrosis, altered myocardial stiffness and finally ventricular dysfunction. Imatinib mesylate blocks receptor tyrosine kinase, which may in turn affect platelet-derived growth factor (PDGF) β-receptor tyrosine phosphorylation. PDGF can also activate cardiac fibroblasts through its unique receptors. We evaluated whether imatinib prevents the cardiac fibrosis and thus improves left ventricle (LV) diastolic dysfunction in spontaneously hypertensive rats (SHR).
Methods and Results: 8 week-old male SHRs (n=18) were randomized into three groups (n=6, respectively): 1. SHRs treated with 8 weeks of low-dose imatinib (SHR-10; 10mg/kg); 2. those with high-dose imatinib (SHR-30; 30mg/kg); 3. those with saline (SHR-C). 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 RT-PCR analyses. 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 LV wall thickness (septal/posterior wall; SHR-C vs. SHR-30: 18±2/19±2 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 TGF-β1 and collagen III, and PDGF β-receptor tyrosine phosphorylation in the hearts of SHR.
Conclusions: These results suggest that imatinib could attenuate cardiovascular remodeling and prevent LV diastolic dysfunction in hypertensive rat model by affecting the action of PDGF in the pressure-overloaded hearts without BP-lowering effect. Imatinib may provide a potential therapeutic approach for hypertensive heart disease.
- © 2011 by American Heart Association, Inc.