Cellular and molecular mechanism of action of raloxifene on vascular tissue

RAUSCHEMBERGER, M.B.; CUTINI, P.; SANDOVAL, M.; POLINI, N.; MASSHEIMER, V.

Buenos Aires

Simposio; XXVII Reunión Anual AAOMM; 2007

AAOMM

Raloxifene (Rx) is a selective estrogen receptor modulator (SERM). Although the use of Rx has been approved for the treatment of postmenopausal osteoporosis, little is known about its vascular effect. In this study, we evaluated whether Rx could modulate the cellular and molecular events associated with atherosclerotic lesions. In rat aortic strips, 5?20 min treatment with 10 nM Rx significantly increased nitric oxide (NO) synthesis, event prevented by the estrogen receptor antagonist ICI 182780 (0.51 ± 0.09 vs. 0.82 ± 0.02; 0.52 ± 0.03 vs. 0.46 ± 0.09 pmol NO/mg prot, control vs. Rx without or with ICI 182780, p < 0.01). This stimulatory action was dependent on PI3K cascade activation, since the presence of LY 294002 (PI3K antagonist) suppressed the enhancement in NO elicited by Rx (61% vs. 2% above control in the absence or presence of 1 mM LY 294002, respectively). When platelet aggregation was evaluated, the SERM exhibited an antiaggregatory action, dependent on the nitric oxide release from endothelial cells. The effect of Rx on cell proliferation was investigated in endothelial cell (EC) and vascular smooth muscle cell (VSMC) cultures by measuring 3H-thymidine incorporation. In EC, Rx (24 h of treatment) significantly inhibited DNA synthesis. In contrast, Rx (1 nM to 10 mM) markedly increase VSMC 3H thymidine uptake, event prevented by the presence ICI 182780. Indeed, Rx also modulated VSMC migration. In summary, the results obtained provide evidence that the mechanism of action of Rx on vascular tissue involves genomic (cell proliferation) and non-genomic action (nitric oxide production) dependent on estrogen receptor participation and PI3K transduction system.