Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations.

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PDI modification by oxLDLs or by reactive carbonyls inhibits its enzymatic activity and potentiates both ER stress and apoptosis by oxLDLs. PDI modification by lipid peroxidation products in atherosclerotic lesions suggests that a loss of function of PDI may occur in vivo, and may contribute to local ER stress, apoptosis, and plaque progression.

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Chronic exposure to ultraviolet (UV) radiation causes oxidative stress, which is involved in photoaging and actinic elastosis. UV and reactive oxygen species generate lipid peroxidation products, including the α, β-unsaturated carbonyl compounds such as acrolein or 4-hydroxynonenal (4-HNE). These aldehydes can modify proteins of the extracellular matrix, but their role in the pathogenesis of photoaging is not clarified. The aim of this study was to investigate whether these aldehydes contribute to alter elastin metabolism and whether topical carbonyl scavengers delay UV-induced skin photoaging. Hairless mice (4-6-week old) daily exposed to UV-A (20 J cm(-2) per day, up to 600 J cm(-2)) exhibited the typical features of photoaging, associated with a significant increase in 4-HNE- and acrolein-adduct content, and elastotic material deposition. Immunofluorescence studies showed the accumulation of 4-HNE adducts on elastin in the dermis of UV-A-exposed mice. This was mimicked in vitro by incubating orcein-elastin with 4-HNE or acrolein, which altered its digestion by leukocyte-elastase, a feature possibly involved in the accumulation of elastotic material. A daily topical application of carnosine completely reversed the development of photoaging alterations and 4-HNE-adduct formation on elastin. These data emphasize the role of 4-HNE and acrolein in the mechanism of photoaging, and the preventive effect of carbonyl scavengers.

BACKGROUND AND PURPOSENeovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial; both angiogenic and anti-angiogenic effects have been reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid, sphingosine 1-phosphate (S1P), in this process is not known. Thus, we investigated whether S1P is involved in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody can prevent this effect. EXPERIMENTAL APPROACHAngiogenesis was assessed by capillary tube formation by human microvascular endothelial cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice. KEY RESULTSHuman oxLDL exhibited a biphasic angiogenic effect on HMEC-1; low concentrations were angiogenic, higher concentrations were cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signalling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentrations of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by i.p. injection of the anti-S1P antibody. CONCLUSION AND IMPLICATIONSThese data highlight the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and demonstrate that the anti-S1P antibody effectively blocks the angiogenic effect of oxLDL.Abbreviations oxLDL, oxidized low-density lipoproteins; S1P, sphingosine 1-phosphate; HMEC-1, human microvascular endothelial cells; SPHK, sphingosine kinase; SPHK1, sphingosine kinase 1; ROS, reactive oxygen species BJP British Journal of Pharmacology

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Opuntia species have been used for thousands of years as a folk medicine in the treatment of diseases. However, the components and protective mechanisms are still unclear. We make the hypothesis that Opuntia species may protect the development of oxidative stress-associated diseases, such as atherosclerosis or colon cancer, via their antioxidant properties. We investigated the protective effect of Opuntia cladode powder against the oxidation of low-density lipoprotein (LDL) evoked by vascular endothelial cells, an important risk factor for atherosclerosis development, and the toxicity of 4-hydroxynonenal (a major lipid peroxidation product) on normal (Apc +/+) and preneoplastic (Apc min/+) immortalized epithelial colon cells. Various Opuntia species classified according to their degree of domestication, from the wildest (Opuntia streptacantha, Opuntia hyptiacantha, Opuntia megacantha), medium (Opuntia albicarpa), to the most domesticated (Opuntia ficus-indica) were tested. Cladode powders prepared from these Opuntia species significantly inhibited LDL oxidation induced by incubation with murine endothelial cells and the subsequent foam cell formation of RAW 264.7 murine macrophages and cytotoxicity on murine endothelial cells. Moreover, Opuntia cladode powder blocked the promotion of colon cancer development on an in vitro model of colonocytes. It may be noted that the phenolic acid and flavonoids content, the antioxidant capacity, and the protective effect were relatively similar in all the cladode powders from wild (O. streptacantha) and domesticated Opuntia. Altogether, these data confirm the therapeutic potential of Opuntia cladodes in diseases associated with oxidative stress.