Induction of apoptosis in vascular smooth muscle cells by mechanical stretch.
We studied the response of porcine vascular smooth muscle cells (PVSMCs) to cyclic sinusoidal stretch at a frequency of 1 Hz. Cyclic stretch with an area change of 25% caused an increase in PVSMC apoptosis, which was accompanied by sustained activation of c-Jun NH(2)-terminal kinases (JNK) and the mitogen-activated protein kinase p38. Cyclic stretch with an area change of 7% had no such effect. Infection of PVSMCs with recombinant adenoviruses expressing constitutively active forms of upstream molecules that activate JNK and p38 also led to apoptosis. The simultaneous blockade of both JNK and p38 pathways with adenovirus-mediated expression of dominant-negative mutants of c-Jun and p38 caused a significant decrease (to 1/2) of the apoptosis induced by 25% cyclic stretch. The 25% stretch also caused sustained clustering of tumor necrosis factor-alpha (TNF-alpha) receptor-1 and its association with TNF-alpha receptor-associated factor-2 (TRAF-2). Overexpressing the wild-type TRAF-2 in PVSMCs caused an increase in apoptosis. In contrast, the expression of a dominant-negative mutant of TRAF-2 attenuated stretch-induced apoptois. These results support the hypothesis that circumferential overload under hypertensive conditions induces a clustering of death receptors that cause vascular smooth muscle cell apoptosis.
Sotoudeh
Mohammad
M
Department of Bioengineering and Whitaker Institute of Biomedical Engineering, Advanced Tissue Sciences, La Jolla, California 92093, USA.
Li
Yi-Shuan
YS
Yajima
Noriyuki
N
Chang
Chih-Chieh
CC
Tsou
Tsui-Chun
TC
Wang
Yibin
Y
Usami
Shunichi
S
Ratcliffe
Anthony
A
Chien
Shu
S
Shyy
John Y-J
JY
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D017209:Apoptosis; D001696:Biomechanical Phenomena; D002460:Cell Line; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney; D048670:MAP Kinase Kinase 4; D008465:Mechanoreceptors / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology*; D009154:Mutation; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D013552:Swine; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases