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 pathophysiolo gical importance in cardiovascular disease. Mechanical forces such as pulsatility may also contribute. Using human coronary artery smooth mu scle 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-acety lcysteine and pyrrolidinedithiocarbamate (PDTC). Pulsatile stretch als o increased superoxide production from HCAS in a time-and stretch-depe ndent manner. Stretch-induced superoxide production was inhibited by d iphenyleneiodoniumchloride, an NADPH oxidase inhibitor, and p-chlorome rcuriphenylsulfonic acid, an NADH oxidase inhibitor, but not by the xa nthine oxidase inhibitor oxypurinol or the cyclooxygenase inhibitor in domethacin. In electrophoretic mobility shift assays, tumor necrosis f actor-alpha activated nuclear factor-kappa B (NF-kappa B) with a peak at approximate to 3 hours, whereas pulsatile stretch showed sustained activation during stimulation for up to 24 hours. The sustained activa tion of NF-kappa B was abolished by cotreatment with N-acetylcysteine or PDTC. Furthermore, treatment of HCAS with antisense p65 and p50 oli godeoxynucleotides of NF-kappa B inhibited stretch-induced DNA synthes is. We propose that pulsatile stretch increases oxidative stress and, in turn, promotes DNA synthesis via NF-kappa B in cultured human coron ary artery smooth muscle cells.