PubMed · 12546978
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Stephani Sutherland. 2003-01-01. Targeting cell migration.. https://doi.org/10.1016/s1359-6446(02)02549-7
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OBJECTIVE: Migration and proliferation of vascular smooth muscle cells (SMCs) contributes to intimal hyperplasia in saphenous vein (SV) bypass grafts, which leads to patency-threatening stenosis. Evidence for the involvement of basement membrane-degrading matrix metalloproteinases (MMPs) and growth factors in mediating SMC migration and proliferation has been presented in a number of in vitro and in vivo models. 3-Hydroxy-3 methylglutaryl CoA reductase inhibitors (statins) are widely used in patients with atherosclerosis and are claimed to have additional effects beyond cholesterol reduction. We therefore examined the effects of simvastatin, a commonly prescribed statin, on the proliferation and migration of cultured human SV SMC and on neointima formation and MMP activity in human SV organ cultures. To clarify its mode of action, we studied in parallel the effects of a specific MMP inhibitor, marimastat. STUDY DESIGN: Human SV specimens were obtained from patients who underwent coronary artery bypass grafting, and were cultured for 14 days in the presence of three concentrations of simvastatin and subsequently processed for measurement of MMP activity and neointimal thickness measurements. Cultured SV SMCs were used to construct growth curves in the presence of 10% fetal calf serum or 10% fetal calf serum supplemented with simvastatin or marimastat. Migration through a Matrigel basement-membrane matrix (invasion) was quantified with modified Boyden chambers. RESULTS: Simvastatin dose dependently reduced neointima formation (P =.004) in association with reduced MMP-9 activity (P =.03). SMC proliferation and invasion also were inhibited with simvastatin (P <.007 and P <.009, respectively). Marimastat dose dependently inhibited SMC invasion (P <.001) but importantly had no effect on SMC proliferation (P >.36). CONCLUSION: For effective control of neointimal development in vivo, a pharmacologic strategy should inhibit both SMC migration and proliferation. The ancillary properties of 3-Hydroxy-3 methylglutaryl CoA reductase inhibitors typified by simvastatin may be important in this regard.
Stromal cell-derived factor 1 alpha (SDF1 alpha) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes. However, the molecular mechanisms regulating SDF1 alpha-driven cell migration are not well defined. In this study, we have explored the roles of the second messenger NO and the transcription factor NF-kappa B in SDF1 alpha-induced T cell migration. SDF1 alpha treatment of Jurkat T cells increased the activity of NO synthase, which catalyzes the generation of NO. We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1 alpha-induced migration, whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration-dependent manner. Furthermore, we observed that inhibitors of the transcription factor NF-kappa B, which is linked to NO signaling pathways, also significantly blocked the SDF1 alpha-induced chemotactic response. However, these compounds did not have a significant effect on SDF1 alpha-induced mitogen-activated protein kinase activity. In addition, the MAP/Erk kinase kinase inhibitor PD98059 did not abrogate SDF1 alpha-induced chemotaxis. AKT, which has been shown to mediate NO production, was also phosphorylated upon SDF1 alpha stimulation. These studies suggest that NO-related signaling pathways may mediate SDF1 alpha-induced chemotaxis, but not mitogen-activated protein kinase activation.
An 8-year-old son (L.A.S.) of consanguineous parents, presented recurrent bacterial infections, vasculitis and extremely low levels of serum C3 (0.15 microg/ml). The classical and alternative pathway haemolytic activities and the generation of opsonins and chemotactic factors derived from the activation of the complement system were markedly affected in the proband's serum. An in vitro addition of purified C3 restored the classical pathway-dependent haemolytic activity of his serum. Autoradiographs of the proband's lipopolysaccharide (LPS)-stimulated and 35S-labelled fibroblast supernatants after that the SDS-PAGE revealed no C3 alpha or beta chains. The amount of C3 mRNA synthesized by the proband's fibroblasts, as evaluated by reverse transcription-polymerase chain reaction (RT-PCR) assays, was greatly reduced.