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.
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 p22(phox), 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 p22(phox) 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 p22(phox) 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 p22(phox) and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22(phox) 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 p22(phox) mRNA production, could play a role in its protective mechanism against OxSt.
Calò
Lorenzo A
LA
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Italy. renzcalo@unipd.it
Zaghetto
Francesca
F
Pagnin
Elisa
E
Davis
Paul A
PA
Semplicini
Andrea
A
Pessina
Achille C
AC
D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009252:NADPH Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D019255:NADPH Oxidases; D009578:Nitrobenzenes; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D010879:Piperazines
D000959:Antihypertensive Agents; D000975:Antioxidants; D004095:Dihydropyridines; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009578:Nitrobenzenes; D010750:Phosphoproteins; D010879:Piperazines; C054218:manidipine; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase