Effect of L-fucose and fucose-rich polysaccharides on elastin biosynthesis, in vivo and in vitro.

With increasing age elastic fibres in human skin are progressively lysed and skin elasticity is also decreasing. Still there is an age-dependent increase of elastic fibre surface density, mostly due to an alteration of the fibres. The present experiments were undertaken to explore if L-fucose and fucose-rich polysaccharides (FROP-s) could influence elastin biosynthesis. We show here, that topical application of a fucose-containing preparation to the skin of hairless rats increased after 4 weeks the elastic fibre surface density by about 40%, shown by quantitative morphology. Using human skin fibroblasts in explant cultures, the addition of L-fucose or of FROP-3 increased the biosynthesis of immunoprecipitable tropoelastin by about 40%. No increase was found however of desmosine-isodesmosine in skin explant cultures after 72 h of incubation. The effect of L-fucose and FROP-3 on the biosynthesis of collagen and non-collagen proteins excreted by the skin explant cultures was also investigated. L-fucose, but not FROP-3, decreased collagen biosynthesis but both increased non-collagen protein biosynthesis. These results show that L-fucose and FROP-3 stimulate tropoelastin biosynthesis in vitro, and elastic fibre formation in vivo. This stimulation concerns also several non-collagen proteins secreted by skin explant cultures. Elastic fibre formation necessitates the simultaneous synthesis of several microfibrillar glycoproteins as well as of tropoelastin. The increased elastic fibre density in the in vivo experiments suggests that this is indeed achieved by L-fucose and FROP-3, further demonstrating their efficiency in the control of age-dependent modifications of connective tissues in general and of skin in particular.

Effects of L-fucose and fucose-rich oligo- and polysaccharides (FROP-s) on collagen biosynthesis by human skin fibroblasts. Modulation of the effect of retinol, ascorbate and alpha-tocopherol.

The action of L-fucose and a fucose-rich oligosaccharide (FROP-3) on skin explant cultures and fibroblast cell cultures, alone or together with three vitamins (A, C, E, often used in topical preparations) was studied, using as criteria collagen accumulation and collagen and non-collagen protein biosynthesis. In order to confirm the results observed, several variants of the chemical procedure were used. Collagen accumulation in cell cultures and (3)H-proline incorporation in proteins and collagen gave comparable results. L-Fucose produced a slight but significant inhibition of collagen accumulation and of incorporation of radioactive proline in cell associated collagen and also modified the ratio of excreted (soluble) to cell- or tissue-bound collagen and non-collagen proteins. The oligosaccharide (FROP-3) did not produce a comparable inhibition of collagen biosynthesis. Both L-fucose and FROP-3 modulated the action of the two above-mentioned vitamins in most experimental conditions used. The combined action of the three vitamins (all-trans retinol, ascorbate, alpha-tocopherol) with L-fucose and even more so with FROP-3 can be considered as favourable for the modulation of the biosynthetic activity of fibroblasts.

Effect of L-fucose and fucose-rich oligo- and polysaccharides (FROP-s) on skin aging: penetration, skin tissue production and fibrillogenesis.

Skin thickness is decreasing with age. This loss concerns both dermis and epidermis, cells and extracellular matrix. We could show here that percutaneous application of an L-fucose-containing preparation produced an increase of skin thickness and a densification of collagen bundles. We also could show that 3H-L-fucose penetrates in the dermis, a prerequisite for the above mentioned favorable pharmacological activities. These results, together with the previous favorable activities on the downregulation of matrix-degrading enzymes, free radical scavenging and increased cell proliferation confirm the favorable action of fucose and fucose-rich polysaccharides (FROP-s) on the skin by slowing down its aging.

Aging of the vascular wall: serum concentration of elastin peptides and elastase inhibitors in relation to cardiovascular risk factors. The EVA study.

The relations of biological markers of extracellular matrix (plasma elastin peptides and elastase inhibitors) to the clinical history of cardiovascular diseases and risk factors for atherosclerosis were examined in a large population study (the EVA Study) on vascular and cognitive aging performed in 1389 men and women aged 59-71 years. A moderate decrease in elastin peptides was observed in women with a self-reported history of coronary heart disease (P < 0.091) and stroke (P < 0.03) as well as with diabetes (P < 0.043). Similar but non-significant trends were found in men. Furthermore, elastin peptides were significantly and positively correlated to HDL-cholesterol and apolipoprotein A1 in both sexes. On the other hand, elastase inhibitor titers were significantly higher in women than in men. A moderate increase was also found in men (P < 0.097) and women (P < 0.068) with a history of coronary heart disease that reached significance level after pooling both sexes (P < 0.014). Furthermore, elastase inhibitor titers were significantly and positively related to fibrinogen and C reactive protein in either sex. No consistent associations were observed between both biological markers of extracellular matrix and age, blood pressure, body mass index and tobacco or alcohol consumption. These results suggest that a decrease in elastin peptides and an increase in elastase inhibitors might be associated with risk factors of atherogenesis as well as with atherosclerosis-related diseases.

Cardiovascular determinants of plasma fibronectin in an elderly population: the EVA study.

Plasma fibronectin was determined in 1262 individuals (742 females, 520 males) aged 59-71 years at the beginning of an epidemiological study on vascular aging (the EVA study) in Nantes, western France. The average values (62.88+/-20.30 mg/100 ml for males, n=520 and 62.15+/-18.85 mg/100 ml for females, n=742) and the distribution of values were comparable for males and females. Significant positive correlations were found in both sexes between plasma fibronectin values and some cardiovascular risk factors such as body mass index, systolic and diastolic blood pressure, total and low density lipoprotein (LDL)-cholesterol, apolipoprotein B, triglycerides and fibrinogen. A significant negative correlation was found with high density lipoprotein (HDL)-cholesterol. No correlation was found between fibronectin values and smoking or alcohol consumption. Multiple regression analysis showed that systolic blood pressure, LDL cholesterol and triglycerides remained significantly associated with plasma fibronectin whereas only marginal associations were found with age, body mass index and fibrinogen. These results are in agreement with previous findings showing a strong increase in fibronectin in atherosclerotic plaques and also the complex formation between fibronectin and LDL. These results substantiate the claim that modifications of the metabolism of extracellular matrix components accompany the atherosclerotic process.

Micro-methods for serial determinations of elastin metabolism parameters in blood plasma and serum.

Micro-methods are described for the serial determinations of elastin metabolism related parameters in human serum or plasma samples: serum elastase activity, elastase inhibitor titers and elastin peptide conc-s. These methods were used in an epidemiological study (the EVA study, " Etude du vieillissement vasculaire") carried out in Nantes, west of France on several thousand individuals. Blood samples obtained from the first-1389 individuals (574 males, 815 females) were used for the determinations. In order to carry out this large number of determinations previously described procedures had to be modified. These methods used for the large serial determinations of the above mentioned three elastin metabolism related serum (or plasma) parameters are described because of their potential interest for serial clinical investigations.

Relation of serum elastase activity to ultrasonographically assessed carotid artery wall lesions and cardiovascular risk factors. The EVA study.

The potential interest of serum elastase activity (SEA) as a marker of vascular aging and atherosclerosis was studied as part of an epidemiological study on vascular and cognitive aging (EVA Study). SEA was measured in 555 men and 774 women aged 59-71 years with a synthetic substrate, suc(ala)3pNA, according to a modified enzyme-linked immunosorbant assay (ELISA)-type procedure. The distribution of SEA-values was skewed to the right in men and women, the mean value was 0.52 +/- 0.55 U/ml in males and 0.43 +/- 0.52 U/ml for females. This difference could be entirely explained by alcohol consumption. SEA increased strongly with alcohol consumption in males and females. It was also positively and significantly correlated with body mass index (BMI) and systolic blood pressure (SBP). SEA significantly decreased with age in men and was not influenced by smoking in either sex. SEA was significantly increased in diabetic men compared with non-diabetics and a similar trend, although not significant, was observed in women. When both sexes were combined, the association between diabetes and SEA was independent of other clinical risk factors. No significant associations were observed with intima-media thickness or atherosclerotic plaques assessed by B-mode carotid ultrasonography. Among biological risk factors, triglycerides (in both sexes) and glucose (in men) appeared the strongest correlates of increase in SEA. In multivariate analysis, independent determinants of an increased SEA were age, alcohol consumption, triglycerides and glucose in men, and alcohol consumption and triglycerides in women.

[Elastolysis, aging and atherogenesis]. / Elastolyse, vieillissement et athérogénèse.

In order to explore the potential role and importance of elastin fiber degradation in atherogenesis we determined in more than 1,400 individuals (males and females between 59 and 71 years of age), [the EVA epidemiological study] serum parameters related to elastin fiber degradation: serum elastase activity, circulating elastin peptides and serum elastase inhibitor titers. Significant correlations were found these between parameters and several other serum constituents considered as risk-factors of atherogenesis--essentially serum lipid-parameters and glycemia as well as several other biological factors. These correlations confirm the validity of the underlying hypothesis concerning the interest of the clinical determinations of these elastin-related parameters and the potential role of the permanent activation of the endothelial elastin-receptor in atherogenesis.