Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases

The present study was designed to investigate whether apoptosis occurs in e arly-stage vein grafts and to determine the mechanisms by which mechanical stress contributes to apoptosis in vascular smooth muscle cells (SMCs). Apo ptosis in vessel walls of mouse vein grafts was confirmed by morphological changes and by terminal deoxynucleotidyl transferase-mediated dUTP-biotin n ick end labeling (TUNEL). TUNEL+ cells in vein grafts 1, 4, and 8 wk postop eratively was 13%, 29%, and 21%, respectively, and apoptosis occurred mainl y in veins grafted to arteries, remaining unchanged in vein-to-vein grafts. When mouse, rat, and human arterial SMCs were cultured on a flexible membr ane and subjected to cyclic strain stress, apoptosis was observed in a time - and strength-dependent manner. All three types of SMCs showed apoptotic d eath as confirmed by TUNEL, propidium iodide, and annexin V staining. To fu rther study the signal pathways leading to apoptosis, activities of p38, a subfamily of mitogen-activated protein kinases (MAPKs), were determined. Me chanical stress resulted in p38 MAPK activation, reaching high levels withi n 8 min. SE 202190, a specific inhibitor for p38 MAPKs, prevented SMC apopt osis in response to mechanical stress. SMC lines stably transfected with a dominant negative rac, an upstream signal transducer, or overexpressing MAP K phosphatase-l, a negative regulator for MAPKs, completely inhibited mecha nical stress stimulated p38 activation and abolished mechanical stress-indu ced apoptosis. Thus, we provide solid evidence that one of the earliest eve nts in venous bypass grafts is apoptosis, in which mechanical stress-induce d p38-MAPK activation is responsible for transducing signals leading to apo ptosis.