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1112 AT2 RECEPTOR STIMULATION IMPROVES CARDIAC FUNCTION 6 WEEKS AFTER EXPERIMENTAL MYOCARDIAL INFARCTION

Objectives: The AT2 receptor agonist Compound 21 (C21) improves cardiac function 7days after myocardial infarction (MI). This study aimed to investigate whether C21 protects the heart in the late stage post MI. Methods: MI was induced by permanent ligation of the left coronary artery. Treatment with C21 (0,03 mg/kg i.p./daily) was started 6 h after MI and continued for 6wks. Hemodynamic parameters were measured at several time points (1,6wks) via transthoracic Doppler echocardiography and intracardiac Samba catheter. The expression of MMP2,9, TIMPs1,2, TGF-beta1 and collagen content were determined in heart tissue. The effect of C21 on MMP activity was additionally studied in fibroblasts cultured from rat heart. MMPs activity was analysed by gelatin zymography. Results: C21 significantly improved systolic and diastolic function 6w after MI in comparison with vehicle group as shown by ejection fraction (68.8 ± 2.8 % vs. 55.7 ± 4.2%; p < 0.05), fractional shortening (40.8 ± 11% vs. 30.9 ± 3%, p < 0.01), LVIDs (4.7 ± 0.28 mm vs. 5.7 ± 0.3 mm; p < 0.01) and E/A ratio (p < 0.05). Moreover, C21 treatment improved dP/dtmax by 55%, early deceleration time and stroke volume. In postinfarcted myocardium, C21 decreased hydroxyproline content (p < 0.05), protein expression of TGF-beta1 (p < 0.05), MMP2 (p < 0.05) and MMP9 (p < 0.05), whereas TIMP-1 was strongly up-regulated (p < 0.001) in comparison to vehicle group. In primary cardiac fibroblasts, C21 reduced the release of cytokine-induced MMP9 (p < 0.001) and decreased mRNA expression. Conclusion: The AT2 receptor agonist C21 improves heart function in the late stage after MI and prevents cardiac remodelling. Inhibition of proteolysis, TGF-beta1 expression and collagen accumulation may attenuate destruction of the extracellular matrix and decrease fibrosis.