Rapamycin-FKBP Inhibits Cell Cycle Regulators of Proliferation in Vascular Smooth Muscle Cells

Abstract

Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33cdk2 kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

“…It is significant that one of these, rapamycin, which has shown much promise in early reports, 11,12 is believed to have significant effects on the immune cells that contribute to in-stent restenosis, 10 in addition to affecting smooth muscle. 28,29 In this paper, we have shown that we can also target both smooth muscle cells and immune cells such as macrophages by use of polymer-coated stents as a means for the delivery of a transgene. It is conceivable that stent-based gene delivery may represent an advantage over therapies based on the elution of small molecules from polymer-coated stents.…”

Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin

“…13,14 known as the mammalian target of rapamycin (mTOR). mTOR inhibition prevents phosphorylation of proteins involved in regulation of the cell cycle leading to arrest at the G1/S interface 15,16 and inhibition of intracellular signaling pathways associated with growth factor stimulation. 17,18 In addition to the effects observed on fibroblasts, immune cells, and hepatocytes, rapamycin inhibits vascular smooth muscle cell proliferation and migration as well as intimal thickening after injury.…”

Immunosuppressive Therapy After Cardiac Transplantation

“…Four decades ago Rapa was extracted and its antifungal effects reported [61]. Intensive research resulted in the discovery of the target of rapamycin named mTOR.…”

“…Both drugs form a complex with the intracellular binding protein FKBP-12, (similar to FK 506) but contrarily to TAC the PSIs inhibit the activity of mTOR. This leads to an arrest of a cell cycle in the mid-to-late G1 phase [61,62]. While FK 506 is suppressing lymphokine production and blocking activation of T-cells, PSIs inhibit cells proliferation by impairing their response to growth-promoting lymphokines [63,64].…”

“…It was discovered in 1965, extracted out of soil taken from Rapa Nui in New Zeeland [65]. Its IS effects were discovered in the 1990s [61]. During the approval studies for Rapa the antitumor effects of Rapa and its analogues like EvE were found introducing them in oncology and for the prevention of restenosis after percutaneous coronary angioplasty.…”