TY - JOUR
T1 - Plasmin induces smooth muscle cell proliferation
AU - Nicholl, Suzanne M.
AU - Roztocil, Elisa
AU - Galaria, Irfan I.
AU - Davies, Mark G.
N1 - Funding Information:
This research was supported by grants for Mark G. Davies, M.D., Ph.D., from the American College of Surgeons Junior Faculty Award and from the Mentored Clinical Scientist Development Award, sponsored by the NIH-NHLBI/Lifeline Foundation (K08 HL 67746), and for Irfan Galaria, MD, from the NIH through a Institutional Research Service Award (T32 HL HL07949). Suzanne Nicholl received grant support from the AHA through a Post Doctoral Fellowship (0225696T).
Funding Information:
Supported by the U.S. Public Health Service HL67746 and HL07949, American College of Surgeons Junior Faculty Award, American Heart Association (NY) 0225696T.
PY - 2005/7/1
Y1 - 2005/7/1
N2 - Background. Plasminogen activators are routinely used for thrombolysis. They lead to the generation of the protease, plasmin, which can induce smooth muscle cell proliferation and may thus promote further intimal hyperplasia in the thrombolysed vessel. The signaling pathways used by plasmin are not understood. Methods. Murine aortic smooth muscle cells were cultured in vitro. Assays of DNA synthesis, cell proliferation, MAPKK and MAPK activation were examined in response to plasmin alone and in the presence of plasmin inhibitors (ε-aminocaproic acid and aprotinin), pertussis toxin (Gαi inhibitor, PTx), GP-2A (Gαq inhibitor), wortmannin (PI3-K inhibitor, Wn), LY294002, (PI3-K inhibitor, LY), PD98059 (MEK inhibitor, PD), and SB203580 (p38 MAPK inhibitor, SB). Results. Plasmin produced concentration dependent smooth muscle cells DNA synthesis and proliferation and induced ERK1/2 and p38MAPK phosphorylation. Inhibition of the proteolytic activity of plasmin prevented these responses. The ERK1/2 inhibitor, PD, but not the p38MAPK inhibitors, SB, blocked cell proliferation. The activation of the MEK1/2 and ERK1/2 pathway was both Gαi dependent (PTx-sensitive) and Gαq dependent (GP-2A-sensitive). It was blocked by the PI3-K inhibitors, Wn and LY. PI3-K activation as measured by akt phosphorylation was dependent on Gαi, but was independent of Gαq. Conclusion. Plasmin induces smooth muscle cell proliferation. Plasmin induced ERK1/2 phosphorylation occurs through two pathways: one which is Gαi mediated/PI3-K dependent and a second which is Gαq mediated/PI3K independent. p38MAPK appears not to be involved in plasmin-mediated cell proliferation. This pattern of activation is distinct from that seen with urokinase plasminogen activator.
AB - Background. Plasminogen activators are routinely used for thrombolysis. They lead to the generation of the protease, plasmin, which can induce smooth muscle cell proliferation and may thus promote further intimal hyperplasia in the thrombolysed vessel. The signaling pathways used by plasmin are not understood. Methods. Murine aortic smooth muscle cells were cultured in vitro. Assays of DNA synthesis, cell proliferation, MAPKK and MAPK activation were examined in response to plasmin alone and in the presence of plasmin inhibitors (ε-aminocaproic acid and aprotinin), pertussis toxin (Gαi inhibitor, PTx), GP-2A (Gαq inhibitor), wortmannin (PI3-K inhibitor, Wn), LY294002, (PI3-K inhibitor, LY), PD98059 (MEK inhibitor, PD), and SB203580 (p38 MAPK inhibitor, SB). Results. Plasmin produced concentration dependent smooth muscle cells DNA synthesis and proliferation and induced ERK1/2 and p38MAPK phosphorylation. Inhibition of the proteolytic activity of plasmin prevented these responses. The ERK1/2 inhibitor, PD, but not the p38MAPK inhibitors, SB, blocked cell proliferation. The activation of the MEK1/2 and ERK1/2 pathway was both Gαi dependent (PTx-sensitive) and Gαq dependent (GP-2A-sensitive). It was blocked by the PI3-K inhibitors, Wn and LY. PI3-K activation as measured by akt phosphorylation was dependent on Gαi, but was independent of Gαq. Conclusion. Plasmin induces smooth muscle cell proliferation. Plasmin induced ERK1/2 phosphorylation occurs through two pathways: one which is Gαi mediated/PI3-K dependent and a second which is Gαq mediated/PI3K independent. p38MAPK appears not to be involved in plasmin-mediated cell proliferation. This pattern of activation is distinct from that seen with urokinase plasminogen activator.
KW - akt
KW - Cell signaling
KW - MAPK
KW - PI3K
KW - Plasmin
KW - Proliferation
KW - Smooth muscle cell
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U2 - 10.1016/j.jss.2005.03.004
DO - 10.1016/j.jss.2005.03.004
M3 - Article
C2 - 15869763
AN - SCOPUS:20444451643
SN - 0022-4804
VL - 127
SP - 39
EP - 45
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -