Qualitative and quantitative modifications of receptors were shown to play a key role in cell and tissue aging. We recently described the properties of a rhamnose-recognizing receptor on fibroblasts involved in the mediation of age-dependent functions of these cells. Using Ca(2+)-mobilization and DNA-microarrays we could show in the presence of rhamnose-rich oligo- and polysaccharides (RROPs) Ca(2+)-mobilization and changes in gene regulation. Here, we compared the effects of several RROPs, differing in their carbohydrate sequence and molecular weights, in normal human dermal fibroblasts (NHDFs). It appeared that different structural features were required for maximal effects on Ca(2+)-mobilization and gene-expression profiles. Maximal effect on Ca(2+) influx and intracellular free calcium regulation was exhibited by RROP-1, a 50 kDa average molecular weight polysaccharide, and RROP-3, a 5 kDa average molecular weight oligosaccharide with a different carbohydrate sequence. Maximal effect on gene-expression profiles was obtained with RROP-3. These results suggest the possibility of several different transmission pathways from the rhamnose-receptor to intracellular targets, differentially affecting these two intracellular functions, with potential consequences on aging. Although of only relative specificity, this receptor site exhibits a high affinity for rhamnose, absent from vertebrate glycoconjugates. The rhamnose-receptor might well represent an evolutionary conserved conformation of a prokaryote lectin.

Le vieillissement des vaisseaux sanguins recouvre un ensemble d’événements touchant aussi bien les cellules que la matrice extracellulaire de la paroi vasculaire. Le vieillissement normal est associé à des processus dégénératifs multiples, tels que : rigidification artérielle liée à la fragmentation des fibres élastiques et l’accumulation de collagènes pariétaux, pontage progressif des fibres de collagène et dérégulation de la vasomotricité liée à un dysfonctionnement des cellules musculaires lisses ou endothéliales. Le vieillissement pathologique, c’est-à-dire n’affectant qu’une partie de la population, peut avoir des conséquences sur tout l’organisme, comme dans l’hypertension, ou avoir des effets plus localisés, comme dans le cas des anévrismes, de l’athérosclérose ou des varices. Certains travaux suggèrent que le mode de vieillissement vasculaire pourrait aussi être lié à l’état initial du système vasculaire. En particulier, il a été montré que des modifications structurales et fonctionnelles de la paroi artérielle liées au déficit en élastine sont capables de modifier à long terme les processus normaux du vieillissement. L’expression précoce de l’élastine apparaît ainsi comme un régulateur du vieillissement artériel. La fonction cardiovasculaire de l’adulte et son évolution au cours du vieillissement, ainsi que la susceptibilité à développer des pathologies cardiovasculaires, dépendent donc étroitement des conditions initiales et notamment du bon déroulement de l’élastogenèse. Ces aspects seront sans doute à prendre en compte dans les futures stratégies thérapeutiques.

An α-l-Rhamnose specific lectin site was described on human skin keratinocytes and fibrobasts. The addition of Rhamnose-rich oligo- and polysaccharides (RROPs) to fibroblasts has been shown to stimulate cell proliferation and increase extracellular matrix biosynthesis, suggesting that this lectin site functions as a “true” receptor transmitting messages to the cell interior. It was confirmed here that addition of the Rhamnose-rich polysaccharide, RROP-1, to normal human dermal fibroblasts (NHDFs) and human endothelial cells produced a dose-dependent stimulation of the calcium-signaling pathway, inducing fast and transient increases in Ca2+ influx and intracellular free Ca2+ level. The Rhamnose-rich oligosaccharide RROP-3 as well as l-Rhamnose alone were also able to trigger similar intracellular free Ca2+ concentration increases in NHDFs. Moreover, the recording of the RROP-1-induced modification of the gene-expression profile in fibroblasts showed that this polysaccharide triggered a down-regulation of the expression of several growth factors, adhesion molecules and extracellular matrix proteins involved in pro-tumoral activity and/or fibrotic processes. These results further support the hypothesis of a receptor function for the Rhamnose-recognizing lectin site in fibroblasts. Anti-fibrotic and anti-tumoral potential of RROP-1 remains to be further explored.

Article history: An α-L-Rhamnose specific le Received 24 December 2007 Received in revised form 5 July 2008 Accepted 10 July 2008 Available online 28 July 2008

Rhamnose-rich oligo- and polysaccharides (RROPs) were tested for their potential pharmacological properties using human skin fibroblasts in serial cultures. The substances tested were shown to stimulate cell proliferation, decrease elastase-type activity, stimulate collagen biosynthesis, and protect hyaluronan against free radical mediated degradation. These reactions appear to be triggered by the mediation of a specific alpha-L-rhamnose recognizing lectin-site acting as a receptor, transmitting signals to the cell-interior. The rapid increase of intracellular free calcium after addition of RROP-1 and preliminary data using micro arrays appear also to confirm this contention.