Pulsatile stretch stimulates superoxide production and activates nuclear factor-kappa B in human coronary smooth muscle.
There is increasing evidence that oxidative stress is of pathophysiological importance in cardiovascular disease. Mechanical forces such as pulsatility may also contribute. Using human coronary artery smooth muscle cells (HCAS), we tested the hypothesis that stretch-induced cell proliferation is associated with oxidative stress. Stretch induced DNA synthesis in HCAS, and this was prevented by the antioxidants N-acetylcysteine and pyrrolidinedithiocarbamate (PDTC). Pulsatile stretch also increased superoxide production from HCAS in a time- and stretch dependent manner. Stretch-induced superoxide production was inhibited by diphenyleneiodoniumchloride, an NADPH oxidase inhibitor, and p-chloromercuriphenylsulfonic acid, an NADH oxidase inhibitor, but not by the xanthine oxidase inhibitor oxypurinol or the cyclooxygenase inhibitor indomethacin. In electrophoretic mobility shift assays, tumor necrosis factor-alpha activated nuclear factor-kappa B (NF-kappa B) with a peak at approximately 3 hours, whereas pulsatile stretch showed sustained activation during stimulation for up to 24 hours. The sustained activation of NF-kappa B was abolished by cotreatment with N-acetylcysteine or PDTC. Furthermore, treatment of HCAS with antisense p65 and p50 oligodeoxynucleotides of NF-kappa B inhibited stretch-induced DNA synthesis. We propose that pulsatile stretch increases oxidative stress and, in turn, promotes DNA synthesis via NF-kappa B in cultured human coronary artery smooth muscle cells.
Hishikawa
K
K
University Hospitals, Bern, Switzerland.
Oemar
B S
BS
Yang
Z
Z
Lüscher
T F
TF
D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000096:biosynthesis*; D013314:Stress, Mechanical; D013481:Superoxides / Q000378:metabolism*
D016328:NF-kappa B; D013481:Superoxides