Abstract P303: Cilostazol Attenuates Angii-induced Cardiac Fibrosis in Mice

Background: Cilostazol, a phosphodiesterase-3 inhibitor, plays vasoprotective roles such as an improvement of endothelial function, a vasodilatation and a suppression of proliferation of vascular smooth muscle cells. The aim of study was to investigate a cardioprotective effect of cilostazol. Method: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal chow diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either angiotensin II (AngII, 1,000 ng/kg/min, n = 16 - 19) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. Results: AngII equivalently increased systolic blood pressure, irrespective of cilostazol administration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. AngII increased heart weight but was attenuated by cilostazol administration (6.7±0.8 to 6.0±0.7 mg/gBW, p < 0.05). Cilostazol prevented both perivascular and interstitial cardiac fibrosis induced by AngII (p < 0.05, each). Quantitative real-time PCR revealed that mRNA expressions of Ctgf , Collagen I , Collagen III , Tgf- , Hgf and Spp-1 increased by AngII infusion but were attenuated by cilostazol administration (p < 0.05). Immunohistochemical analysis demonstrated that AngII administration enhanced OPN expression in heart but was suppressed by cilostazol administration. Further, to investigate the mechanism, human cardiac myocytes were cultured and stimulated with AngII (1x10 -7 M). Co-treatment of Cilostazol (1x10 -7 to 1x10 -5 M) attenuated AngII-induced increase of Spp-1 gene expression in dose-dependent manner. This effect was mimic by a treatment with forskolin, which was diminished by co-treatment with H-89. Conclusion: Cilostazol attenuated AngII-induced cardiac fibrosis in vivo. Cilostazol attenuated AngII-induced increment of Spp-1 gene expression through cAMP-PKA dependent pathway.