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Abstract
We have reported previously that dihydropyridine-type calcium-channel antagonists (DTCCA) such as nifedipine decrease plasma markers of oxidative stress damage in systemic sclerosis (SSc). To clarify the cellular basis of these beneficial effects, we investigated the effects in vivo and in vitro of nifedipine on superoxide anion (O2•-) production by peripheral blood monocytes. We compared 10 healthy controls with 12 patients with SSc, first after interruption of treatment with DTCCA and second after 2 weeks of treatment with nifedipine (60 mg/day). O2•- production by monocytes stimulated with phorbol myristate acetate (PMA) was quantified by the cytochrome c reduction method. We also investigated the effects in vitro of DTCCA on O2•- production and protein phosphorylation in healthy monocytes and on protein kinase C (PKC) activity using recombinant PKC. After DTCCA had been washed out, monocytes from patients with SSc produced more O2•- than those from controls. Nifedipine treatment considerably decreased O2•- production by PMA-stimulated monocytes. Treatment of healthy monocytes with nifedipine in vitro inhibited PMA-induced O2•- production and protein phosphorylation in a dose-dependent manner. Finally, nifedipine strongly inhibited the activity of recombinant PKC in vitro. Thus, the oxidative stress damage observed in SSc is consistent with O2•- overproduction by primed monocytes. This was decreased by nifedipine treatment both in vivo and in vitro. This beneficial property of nifedipine seems to be mediated by its cellular action and by the inhibition of PKC activity. This supports the hypothesis that this drug could be useful for the treatment of diseases associated with oxidative stress.
Highlights
Systemic sclerosis (SSc) is a connective tissue disease, characterised by vascular involvement with generalised microangiopathy culminating in systemic fibrosis
We investigated the effects of nifedipine in vitro on O2- release from human monocytes, on protein phosphorylation with phorbol myristate acetate (PMA) as stimulator and on protein kinase C (PKC) activity
Nifedipine produced a significantly greater amount of O2than controls (n = 10) after stimulation ex vivo with the PKC activator PMA for 15 min
Summary
Systemic sclerosis (SSc) is a connective tissue disease, characterised by vascular involvement with generalised microangiopathy culminating in systemic fibrosis. Several lines of evidence suggest that the generation of oxygen free radicals is of major importance in the pathogenesis of SSc [1]. Frequent episodes of reperfusion injury generate oxygen free radicals locally, but increased lipid peroxidation is not related to Raynaud's phenomenon only [2] and the inflammatory process might generate oxidative stress [1]. Histological studies of cutaneous SSc lesions have revealed early mononuclear cell infiltration of perivascular spaces around small vessels [3,4], and mononuclear cells might affect vascular and tissue lesions by producing various molecules [5]. Monocytes from patients with SSc produce greater amounts of superoxide anion (O2-) than those from healthy subjects and patients with primary Raynaud's phenomenon [7]
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