Basic fibroblast growth factor protects cardiac myocytes from iNOS-mediated apoptosis

Basic fibroblast growth factor (bFGF) is an important angiogenic factor pro duced by hearts subjected to ischemia. However, the direct effects of bFGF on myocardial cells are unknown. Primary cultured cardiac myocytes from neo natal rats were stimulated with lipopolysaccharide (LPS), a potent inducer of inducible nitric oxide synthase (iNOS), in the presence or the absence o f bFGF. LPS induced the expression of iNOS in cardiac myocytes, demonstrate d at both mRNA and protein levels. We showed that LPS activated the apoptot ic pathway, evidenced by TUNEL staining, DNA ladder formation, and morpholo gic features. LPS-induced apoptosis was blocked by the administration of L- NAME, an inhibitor of NOS. This indicates that LPS induces apoptosis via an iNOS-dependent pathway. Administration of bFGF completely inhibited myocar dial cell apoptosis induced by hydrogen peroxide or acidic medium as well a s LPS. To determine signaling pathways for this inhibitory effect, We utili zed PD098059, an MEK-1-specific inhibitor. PD098059 blocked bFGF-induced ac tivation of ERK (extracellularly responsive kinase)-1/2 and neutralized the apoptotic inhibitory effect of bFGF. These findings demonstrate that LPS i nduces myocardial cell apoptosis in an iNOS-dependent manner. The results a lso suggest that bFGF is a protective factor against myocardial cell apopto sis and that this protection requires the MEK-1-ERK pathway. (C) 2002 Wiley -Liss, Inc.