Prominent angiopathologic events associated with hypertrophy and ischemia are accompanied by secretion of growth factors from reactive cells. The maintenance of endothelial integrity includes the responsibility of acidic fibroblast growth factor (FGF-1), an angiogenic polypeptide lacking a classical signal sequence for secretion. Recent evidence from this laboratory has defined a nonconventional pathway for cellular secretion of FGF-1 that is induced by oxidative stress associated with inflammation and mediated by superoxide, nitric oxide, and their reaction product, peroxynitrite. During this process, FGF-1 modulates the induction of oxidant-mediated apoptosis, an observation accompanied by the appearance of select polypeptides containing nitrated tyrosine residues. Collectively, these observations imply a central role for FGF-1 during resolution of inflammation and repair. Experimental aims are designed within the framework of the hypothesis that in response to oxidative stress, FGF-1 mediates its transforming potential through an extracellular pathway which can be attenuated with specific antioxidant agents. An underlying theme includes quantitating the production and targeted molecular responses to reactive nitrogen/oxygen species in vitro that modulate antioxidant defense mechanisms and FGF-1 signal transduction pathways. The availability of antibodies, nucleic acid probes/amplimers, recombinant proteins, expression vectors, and established techniques permits fundamental mechanistic studies of responding molecular cascades by analyses of mRNA (RT-PCR, hybridization) and protein (Western, ELISA, immunohistochemistry, enzymatic activity) expression. The opportunity to dissect and modulate key FGF-1 and oxidant-induced responses in defined vascular cells is complemented by the ability to extend these observations into relevant rodent models of hypertrophy and ischemia reperfusion injury. Elucidation of the molecular events responsible for the cause and effect relationship between oxidant stress and FGF-1 secretion and biologic activity will reveal detailed characteristics of these interrelationships, provide diagnostic criteria for monitoring this process, and establish more rational strategies of therapeutic intervention.
Showing the most recent 10 out of 51 publications
