Beneficial role of alendronate on cellular and molecular processes involved in calcification/vascular remodeling

Abstract

The genesis of the atheromatous lesion involves the interaction of monocytes and platelets with the endothelium. Finally, vascular calcification takes place through vascular smooth muscle cells (VSMC) transdifferentiation to bone lineage. The impact of bisphosphonates (BP) on cardiovascular diseases remains unknown. The aim of this study was to investigate the role of the BP alendronate (ALN) in cellular and molecular processes involved in vascular disease. Murine cultures cells were used: a) endothelial cells (EC); b) VSMC; c) VSMC induced to osteoblastic transdifferentiation (VSMC-OB) in osteogenic medium (β-glicerolfostato 5 mM; CaCl2 and 4 mM). The effect of ALN on platelet adhesion (PAd) and aggregation (PAg) was investigated. Under basal conditions ALN partially reduced PAd (20–35%; ALN 1–10 μM; p<0.01). The stimulus induced by LPS was partially reduced in the presence of the BP (22–33%; ALN 1–10 μM; p<0.02). We found that ALN markedly inhibited PAg compared with control (56%; ALN 10 μM; p<0.05). Both antiplatelet effects evoked by ALN were reversed in the presence of L-NAME, an inhibitor of nitric oxide synthase. Monocyte adhesion to EC depends on the expression of adhesion molecules. ALN treatment significantly prevents the enhancement of ICAM-1 and VCAM-1 mRNA levels induced by LPS. On VSMC-OB, ALN markedly reduce the expression of RUNX2 and TNAP, showed a significant diminution in FAL activity (9–29%; ALN 1–10 μM; p<0.02), as well as in extracellular calcium deposition (341 ± 33 vs 225 ± 24 μg/mg prot.; control vs ALN 5 μM; p<0.05). In summary, the results suggest that ALN is an active drug at vascular level with potential beneficial effects on processes that compromise the vascular architecture.