Exacerbated vein graft arteriosclerosis in protein kinase C delta-null mice

Smooth muscle cell (SMC) accumulation is a key event in the development of atherosclerosis, including vein bypass graft arteriosclerosis. Because memb ers of the protein kinase C (PKC) family signal cells to undergo proliferat ion, differentiation, or apoptosis, we generated PKC delta knockout mice an d performed vein bypass grafts on these animals. PKC delta (-/-) mice devel oped normally and were fertile. Vein segments from PKC delta (-/-) mice iso grafted to carotid arteries of recipient mice of either genotype led to a m ore severe arteriosclerosis than was seen with PKC delta (+/+) vein grafts. Arteriosclerotic lesions in PKC delta (-/-) mice showed a significantly hi gher number of SMCs than were found in wild-type animals; this was correlat ed with decreased SMC death in lesions of PKC delta (-/-) mice. SMCs derive d from PKC delta (-/-) aortae were resistant to cell death induced by any o f several stimuli, but they were similar to wild-type SMCs with respect to mitogen-stimulated cell proliferation in vitro. Furthermore, pro-apoptotic treatments led to diminished caspase-3 activation, poly(ADP-ribose) polymer ase cleavage, and cytochrome c release in PKC delta (-/-) relative to wild- type SMCs, suggesting that their apoptotic resistance involves the loss of free radical generation and mitochondrial dysfunction in response to stress stimuli. Our data indicate that PKC delta maintains SMC homeostasis and th at its function in the vessel wall per se is crucial in the development of vein graft arteriosclerosis.