SynopsisDeimination (or citrullination) is a recently described post-translational modification, but its consequences are not yet well understood. It is catalysed by peptidylarginine deiminases (PADs). These enzymes transform arginyl residues involved in a peptidyl link into citrullyl residues in a calciumdependent manner. Several PAD substrates have already been identified like filaggrin and keratins K1 and K10 in the epidermis, trichohyalin in hair follicles, but also ubiquitous proteins like histones. PADs act in a large panel of physiological functions as cellular differentiation or gene regulation. It has been suggested that deimination plays a role in many major diseases such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease and psoriasis. Five human genes (PADIs), encoding five highly conserved paralogous enzymes (PAD1-4 and 6), have been characterized. These genes are clustered in a single locus, at 1p35-36 in man. Only PAD1-3 are expressed in human epidermis. PADs seem to be controlled at transcriptional, translational and activity levels and they present particular substrate specificities. In this review, we shall discuss these main biochemical, genetic and functional aspects of PADs together with their pathophysiological implications. Ré suméLa désimination (ou citrullination) est une modification post-traductionnelle catalysée par les peptidylarginine désiminases (PADs), décrite depuis peu et dont les conséquences sont encore mal comprises. Ces enzymes transforment, de façon dépendante du calcium, les résidus arginyl engagés dans un lien peptidique en résidus citrullyl. Plusieurs substrats ont été identifiés: la filaggrine et les cytokératines K1 et K10 de l'épiderme, la trichohyaline dans le follicule pileux mais aussi des protéines ubiquistes comme les histones. Les PADs interviennent dans de nombreuses fonctions physiologiques telles que la différenciation cellulaire ou la régulation génique. La désimination pourrait jouer un rôle dans plusieurs maladies sévères et fréquentes comme la polyarthrite rhumatoïde, la sclérose en plaque, la maladie d'Alzheimer ou encore le psoriasis. Cinq gènes humains (PADIs) codant pour 5 enzymes paralogues conservées (PAD1-4 et 6) ont été caractérisés. Ils sont regroupés en un seul locus, en 1p35-36 chez l'homme. Seules les PAD1-3 sont exprimées dans l'épiderme humain. Les PADs semblent contrôlées aux niveaux transcriptionnel et Correspondence: Marie-Claire Méchin, UMR5165, Faculté de Médecine,
Vascular calcification is a hallmark of advanced atherosclerosis, but the underlying mechanisms remain unknown. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells (vSMCs) of Low Density Lipoprotein receptor (LDLr) deficient mice fed an atherogenic high-cholesterol diet results in accelerated vascular calcification with chondrogenic metaplasia within the lesions. We demonstrate that vascular calcification in the absence of PPARγ requires the transmembrane receptor Low Density Lipoprotein receptor-related protein-1 (LRP1). LRP1 promotes a previously unknown Wnt5a dependent prochondrogenic pathway that activates the chondrogenic program. PPARγ protects against vascular calcification by activating sFRP2, which we show functions as a Wnt5a antagonist. Thus, targeting this signaling pathway has important clinical implications, impacting on common complications of atherosclerosis including coronary artery calcification and valvular sclerosis.
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