Vascular response to stress: Protective action of the bisphosphonate alendronate.

BACKGROUND: Since several additional actions of bone bisphosphonates have been proposed, we studied the effect of the bisphosphonate alendronate (ALN) on the vascular response to environmental stress. METHODS: Primary cultures of endothelial cells (EC) and vascular smooth muscle cells (VSMC) exposed to strained conditions were employed for experimental evaluation. After ALN treatment, cell migration, proliferation, and angiogenesis assays were performed. The participation of signal transduction pathways in the biochemical action of ALN was also assessed. RESULTS: In VSMC cultures, ALN counteracted the stimulation of cellular migration elicited by the proinflammatory agent lipopolysaccharide (LPS) or by high levels of calcium and phosphorus (osteogenic medium). Indeed, ALN reduced the increase of VSMC proliferation evoked by the stressors. When LPS and osteogenic medium were added simultaneously, the enhancement of cell proliferation dropped to control values in the presence of ALN. The mechanism of action of ALN involved the participation of nitric oxide synthase, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) signaling pathways. The study revealed that ALN exhibits a proangiogenic action. On EC, ALN enhanced vascular endothelial growth factor (VEGF) synthesis, and induced capillary-like tube formation in a VEGF-dependent manner. The presence of vascular stress conditions (LPS or osteogenic medium) did not modify the proangiogenic action elicited by ALN. CONCLUSION: The findings presented suggest an extra-bone biological action of ALN, which could contribute to the maintenance of vascular homeostasis avoiding cellular damage elicited by environmental stress.

N-acetylcysteine as a potential strategy to attenuate the oxidative stress induced by uremic serum in the vascular system.

AIMS: Chronic kidney disease (CKD) progression is accompanied by systemic oxidative stress, which contributes to an increase in the risk of cardiovascular diseases (CVDs). N-acetylcysteine (NAC) is among the most studied antioxidants, but its therapeutic benefits in CKD-associated CVDs remain controversial. Here, we investigated whether NAC could inhibit the oxidative stress induced by uremia in vitro and in vivo. MAIN METHODS: Endothelial and smooth muscle cells were challenged with human uremic or non-uremic sera, and the effects of a pre-treatment with 2mM NAC were evaluated. Reactive oxygen species (ROS) production, protein oxidation and total glutathione/glutathione disulfide (tGSH/GSSG) ratios were measured. Five-sixths nephrectomized or sham-operated rats were orally treated (in the drinking water) with 60 mg/kg/day NAC or not treated for 53 days. Plasma cysteine/cystine reduction potential Eh(Cyss/2Cys) was determined as a novel marker of the systemic oxidative stress. KEY FINDINGS: NAC inhibited all the determined oxidative stress parameters, likely by increasing the tGSH/GSSG ratio, in both cell lines exposed to uremic serum. Orally administered NAC attenuated the systemic oxidative stress in uremic rats. SIGNIFICANCE: The present results indicate that NAC, by preventing GSH depletion in vascular cells exposed to uremic serum and by attenuating the systemic oxidative stress during CKD progression, emerges as a potential strategy to prevent the oxidative stress induced by uremic toxicity in the vascular system.