PDE4 저해제에 의한 심장허혈 : 재관류 손상 예방효과 분석 및 이의 분자생물학적 기전 연구

초록

Purpose : Phosphodiesterase-4(PDE4) inhibitor blocks the hydrolysis of cAMP via inhibition of PDE4 and is attractive candidates for novel anti-inflammatory drugs. However, its function in cardiovascular diseases and cardiomyocyte apoptosis is unclear. Therefore, we investigated whether roflumilast, a PDE4 inhibitor, exerts protective effect against NO-induced apoptosis in neonatal rat cardiomyocytes(NRCMs). Methods : Rat cardiomyocytes were isolated from young heart and induced apoptosis by treatment of NO donor. We used roflumilast and rolipram and cilomilast as a PDE4 inhibitors. Western blot analysis were used for elucidating the protective mechanisms of PDE4 inhibitors. Also, cAMP activity assay, GST-pulldown assay and siRNA transfection were additionally for this study. Results : Roflumilast, rolipram and cilomilast inhibited SNP-induced apoptosis and this effect was reversed by PKA specific inhibitor H-89 and KT-5720. indicating that these inhibitors protects SNP-induced apoptosis via PKA-dependent pathway. These inhibitors increased Epacl/Rap1GTP, and the protective effect was abolished by Epac1 siRNA transfection, demonstrating that Epac signaling was also involved in this protective response. Conclusions : In conclusion, our data indicate that PDE4 inhibitors(roflumilast, rolipram and cilomilast) protects NO-induced apoptosis via both cAMP-PKA/CREB and Epac/Akt-dependent pathway. Our study suggests a possibility of PDE4 inhibitor roflumilast as a potential therapeutic agent against myocardial I/R injury.

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