Suppression of gelatinase activity in human peripheral blood mononuclear cells by verapamil

ABSTRACT

Gelatinases are a large group of proteolytic enzymes that belong to the matrix metalloproteinases [MMPs]. MMPs are a broad family of peptidases, which proteolyse the extracellular matrix and have an important role in inflammation. Verapamil is a calcium channel blocker extensively used in the treatment of numerous cardiovascular diseases such as arrhythmia and hypertension. The anti-tumor and anti-inflammatory effects of verapamil have also been shown. In this study, the effect of verapamil on gelatinase activity in human peripheral blood mononuclear cells [PBMCs] has been assessed in vitro. In this experimental study, PBMCs from healthy adult volunteers were isolated by ficoll-hypaque-gradient centrifugation. The cells were then cultured in complete RPMI-1640 medium and after that incubated with different concentrations of verapamil [0-200 Mirco M] in the presence or absence of phytoheamagglutinin [PHA] [10 Mirco g/ml] for 48 hours. The gelatinase A [MMP-2]/gelatinase B [MMP-9] activity in cell-conditioned media was then evaluated by gelatin zymography. Statistical comparisons between groups were made by analysis of variance [ANOVA]. Verapamil significantly decreased the MMP-2/MMP-9 activity in human PBMCs after 48 hours incubation time compared with untreated control cells. The association was dose-dependent. In this study verapamil exhibited a dose-dependent inhibitory effect on gelatinase A and gelatinase B activity in human PBMCs. It seems that the anti-inflammatory properties of verapamil may be in part due to its inhibitory effects on gelatinase activity. Regarding the beneficial effects of MMPs- inhibitors in the treatment of some cardiovascular diseases, the positive effect of verapamil on such diseases may be in part due to its anti-MMP activity. Verapamil with its inhibitory effects on gelatinases activity may be a useful MMP-inhibitor. Given the beneficial effect of MMP-inhibitors in some cancerous, inflammatory and autoimmune disorders, it seems likely that verapamil could also be used to treat these diseases