Phosphodiesterase 4 (PDE4) inhibitor has been demonstrated to be effective in airway inflammatory diseases however, its role in cardiovascular diseases has not been explored. Here, we investigated whether roflumilast, a specific PDE4 inhibitor, has a protective effect against NO-induced apoptosis in cardiomyocytes. Treatment with Roflumilast (20 min) increased intracellular cAMP levels and inhibited NO donor sodium nitroprusside (SNP)-induced apoptosis in H9c2 cells in a dose dependent manner. In addition, cAMP analogue db-cAMP and PKA specific activator 6Bnz-cAMP mimicked the effects of roflumilast. We tested which downstream molecule of cAMP involved the protection against NO-induced apoptosis. Incubation of cells with roflumilast increased Epac (exchange protein directly activated by cAMP). Furthermore, Epac specific activator 8CPT-cAMP protected SNP-induced apoptosis and knockdown of epac1 gene expression abrogated protective effects of roflumilast, suggesting Epac signaling pathway was involved in this response. Roflumilast phosphorylated both CREB and Akt that was attenuated by PKA inhibitors (H-89 and KT-5720) and PI3 kinase inhibitor (LY294002), which also abolished protective abilities of Roflumilast. However, LY294002 completely inhibited Akt phosphorylation without affecting the phosphorylation of CREB, whereas inhibition of PKA by H-89 blocked the phosphorylation of CREB without affecting the phosphorylation of Akt. 8CPT-cAMP treatment increase Akt phosphorylation only while 6Bnz-cAMP activated CREB only, indicating PKA-CREB and Epac-Akt pathways were independent. In summary, our study suggests that roflumilast has protective effects against the NO-induced apoptosis via cooperation of at least two different signaling pathways: a PKA-CREB and Epac-Akt dependent pathway, leading to protection. Key words; PDE4 inhibitor, Roflumilast, protein kinase A (PKA), exchange protein directly activated by cAMP (Epac)