NGF EXHIBITS A PRO-APOPTOTIC ACTIVITY FOR HUMAN VASCULAR SMOOTH-MUSCLE CELLS THAT IS INHIBITED BY TGF-BETA-1

Apoptosis of vascular smooth muscle cells (SMCs) has been described in culture and also during remodelling of the artery following injury, H owever, the mediators that regulate apoptosis in SMCs are unknown, Bec ause neurotrophins, a family of related polypeptide growth factors, in cluding nerve growth factor (NGF) and its cognate receptor TrkA have b een shown to be strongly expressed in atherosclerotic lesions, the pre sent study was undertaken to evaluate in vitro, the activity of NGF wi th regard to apoptosis of confluent cultures of human aortic SMCs, We report here that NGF induced apoptosis of SMCs in a dose-dependent man ner, This effect,vas detected from the concentration of 1 ng/ml and re ached a maximum at 100 ng/ml, The concentration that induced a half-ma ximum effect was 8.8 ng/ml, The pro-apoptotic activity of NGF was time dependent and was significant after 3 h of incubation, The proapoptot ic activity of NGF was blocked in a dose-dependent manner by K-252a, a n inhibitor of TrkA tyrosine phosphorylation, suggesting that a NGF/Tr kA signal transduction pathway could activate apoptotic cell death pro grams in human SMCs, Significantly, NGF-induced apoptosis was inhibite d by wortmannin and PD 98059, showing that both PI3 kinase and MEK kin ase were involved, At a NGF concentration that strongly induced apopto sis (100 ng/ml), TGF beta 1 which has been identified several times as a protective factor, dose dependently inhibited the pro-apoptotic eff ect of NGF, The IC50 value was 1.5 ng/ml, These results indicate that, at least in vitro, TGF beta 1 can inhibit the pro-apoptotic activity of NGF for SMCs therefore suggesting that TGF beta 1 has the capacity to diminish the deleterious consequences of an excitotoxic or ischemic injury that might occur during atherogenesis or following angioplasty . (C) 1997 Federation of European Biochemical Societies.