Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages.

During normal tissue homeostasis apoptotic cells (AC) are rapidly recognised and engulfed by neighbouring cells or macrophages (Mphi), thus preventing an inflammatory response. Conversely, in chronically inflamed tissues, including the atherosclerotic artery and rheumatoid joint, removal of AC is defective despite the co-localisation of seemingly adequate numbers of Mphi. Mechanisms preventing removal of AC in vivo remain obscure, but might include oxidised low-density lipoprotein (ox-LDL), which is abundant in chronic inflammatory lesions. Although implicated in their pathogenesis, defining the role of ox-LDL on inflammatory processes has proved complicated. In fact, seemingly contradictory results have previously been described, though these may in part reflect the heterogeneous nature of ox-LDL applied in these studies. We wished to investigate the effect of physiologically representative ox-LDL on the binding and engulfment of apoptotic vascular smooth muscle cells (VSMC) and fibroblasts, as these have previously been shown to co-localise with Mphi in chronically inflamed tissues in vivo. We show that Mphi recognition of AC in vitro is not affected at physiological levels of ox-LDL. However, engulfment of intact AC is dramatically reduced/delayed. Importantly, in the absence of ox-LDL rapid phagocytosis of intact AC suppresses Mphi inflammatory cytokine release. In striking contrast, in the presence of ox-LDL, despite binding of AC to Mphi, release of IL-6 and MCP-1 is no longer suppressed. We propose that ox-LDL could maintain an inflammatory response by inhibiting the engulfment of AC, required for Mphi de-activation. This mechanism may contribute to chronic persisting inflammation in the atherosclerotic artery and rheumatoid joint.

Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice.

Anti-angiogenic therapy reduces both plaque growth and intimal neovascularization in apolipoprotein-E-deficient mice (apoE-/-). Vascular endothelial growth factor (VEGF) has been suggested as playing a role in the development of atherosclerosis. We examined the hypothesis that VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated in apoE-/- and, since it could be driven by oxidative stress, tested whether dietary supplementation with vitamins C and E could downregulate it.Two-month-old apoE-/- received vitamin C combined with alpha- or beta-tocopherol for 4 weeks. Aortic VEGF and VEGFR-2 expression were measured by RT-qPCR and western blot.ApoE-/- showed significantly higher expression of aortic VEGF and VEGFR-2 mRNA (P<0.001) and protein (P<0.001) than wild-type mice, as well as increased plasma VEGF (P<0.001). Vitamin C and alpha-tocopherol significantly reduced aortic VEGF and VEGFR-2 expression in apoE-/- (P<0.001), circulating VEGF (P<0.01) and plasma lipid peroxidation (P<0.01). apoE-/- receiving vitamin C and beta-tocopherol showed diminished lipid peroxidation and VEGFR-2, but only partial reduction of VEGF expression. These data demonstrate that augmented VEGF and VEGFR-2 expression in apoE-/- vasculature can be downregulated by vitamins C and E, at least partially through oxidative stress reduction. This novel mechanism could contribute to explaining the beneficial effects of antioxidant vitamins in experimental atherosclerosis.

Effect of cilazapril with or without low dose thiazide on LDL peroxidation in [correction of peroxidationin] hypertensive patients.

BACKGROUND: This study aims to address the question, "Does equivalent blood pressure (BP) reduction by cilazapril alone or in combination with low dose of both cilazapril and hydrochlorothiazide have an equal effect on lowering oxidation of plasma LDL?" METHODS: Fifteen patients with untreated arterial hypertension were enrolled. Patients received 5 mg/d cilazapril (C5) for 6 weeks and were treated with a combination of 2.5 mg/d cilazapril and 12.5 mg/d hydrochlorothiazide (C2.5,HCTz) for an additional 2 months to achieve the same BP reduction as in the initial period. Treatment with a combination of 5 mg/d cilazapril and 12.5 mg/d hydrochlorothiazide (C5,HCTz) was administered for an additional 6 weeks. RESULTS: Treatment with C5 or in combination with C2.5,HCTz lowered systolic BP by the same magnitude (P <.05). Treatment with C5,HCTz decreased systolic BP an additional 7% and diastolic BP by 6% (P <.05). The LDL of 15 hypertensive patients demonstrated a 16.7% shorter lag time to initiation of peroxidation and 8.5% higher malonyldialdehyde levels at point of maximal peroxidation than LDL from 10 healthy controls (P <.05). Treatment with C5 decreased LDL tendency to peroxidation (lag time was prolonged by 43%, P <.05; malonyldialdehyde levels decreased by 8.3%). The combined treatment of C2.5,HCTz achieved the same BP reduction, but did not increase LDL resistance to peroxidation. Treatment with C5,HCTz achieved the same reduction in malonyldialdehyde levels in LDL than C5 therapy, but prolonged lag time by 17% (P <.05). CONCLUSIONS: The decreased tendency of LDL to peroxidation in hypertensive patients treated by cilazapril is due to the inherent effect of cilazapril, and not to a reduction in BP.

Atividade antioxidante de espécies medicinais da família Piperaceae: Pothomorphe umbellata (L) Miq e Piper regnellii (Miq) CDC / Antioxidant activity species medicinals of Piperaceae family: Pothomorphe umbellata (L) Miq and Piper regnellii (Miq) CDC

As plantas medicinais constituem importantes recurso terapêutico no tratamento da saúde humana, principalmente das nações em desenvolvimento. Servem tanto à conhecida "medicina caseira", que faz parte da cultura popular destes países, como de matéria prima para elaboração de medicamentos fitoterápicos ou extração de compostos químicos farmacologicamente ativos. O presente trabalho estuda duas espécies medicinais da família Piperaceae, conhecida popularmente como pariparoba, e usadas para o tratamento de problemas do fígado: Piper regnellii (Miq.) D.CD. e Pothomorphe umbellata (L.) Miq., esta inscrita na primeira edição da Farmacopéia Brasileira. Foram avaliadas, comparativamente, as capacidades antioxidantes...