Effect of Manidipine on Gene Expression and Protein Level of Oxidative Stress-Related Proteins: p22phox and HO-1: Relevance for Antihypertensive and Anti-Remodeling Effects


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Abstract

Oxidative stress (OxSt) is a major damaging factor in arterial hypertension and its long-term complications. This is why considerable attention is paid to the possible effects of antihypertensive drugs on OxSt. Manidipine is a dihydropiridine calcium channel blocker with reported nephroprotective activities, but no information is available on its effect on OxSt and related mechanisms.This study assessed the effect of manidipine on normal subjects’ monocyte gene and protein expression of OxSt-related proteins such as p22phox, a NAD(P)H oxidase system subunit, critical in generating O2, and heme oxygenase-1 (HO-1), induced by and protective from OxSt, and compared manidipine with the ACE inhibitor captopril and the calcium channel blocker nifedipine, in the presence and absence of sodium arsenite (NaAsO2) as an inducer of OxSt.Co-incubation of manidipine with NaAsO2 dose-dependently decreased p22phox mRNA production from basal: 0.87 ± 0.1 d.u., 0.69 ± 0.06 and 0.66 ± 0.09 at 100, 300 and 500 nM respectively versus 0.99 ± 0.2, P < 0.04, while HO-1 mRNA production was increased by the same concentrations of the drug: 0.87 ± 0.1 d.u., 0.92 ± 0.1, 0.98 ± 0.1 respectively versus 0.63 ± 0.07; P < 0.03. Monocyte p22phox mRNA production was reduced both by manidipine and captopril: 0.48 ± 0.04 d.u. and 0.43 ± 0.08, respectively versus 0.58 ± 0.07, P < 0.006, while no changes were induced by nifedipine (0.61 ± 0.07, P = ns). Manidipine increased monocyte HO-1 mRNA production (1.6 ± 0.4 versus 1.2 ± 0.4, P < 0.008), while nifedipine and captopril showed no effect (1.2 ± 0.3 and 1.1 ± 0.3, respectively). The effects of M on p22phox and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22phox and increases HO-1 mRNA production and protein level. The manidipine-induced increase of HO-1 gene and protein expression seems to be a peculiar effect of this drug since it is not observed with captopril and nifedipine. This effect, together with the reduction of p22phox mRNA production, could play a role in its protective mechanism against OxSt.

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