RESUMO
RATIONALE: S100A12 is a small calcium binding protein that is a ligand of RAGE (receptor for advanced glycation end products). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear. OBJECTIVE: To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the smooth muscle 22alpha promoter because S100A12 is not present in mice. METHODS AND RESULTS: Transgenic mice displayed pathological vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent matrix metalloproteinase-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12 mediates increased interleukin-6 production, activation of transforming growth factor beta pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells. CONCLUSIONS: S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo.
Assuntos
Aneurisma Aórtico/metabolismo , Músculo Liso Vascular/metabolismo , Estresse Oxidativo , Proteínas S100/biossíntese , Vasculite/metabolismo , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Células Cultivadas , Colágeno/biossíntese , Colágeno/genética , Tecido Elástico/metabolismo , Tecido Elástico/patologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Liso Vascular/patologia , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/agonistas , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteínas S100/genética , Proteína S100A12 , Fibras de Estresse/genética , Fibras de Estresse/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Vasculite/genética , Vasculite/mortalidadeRESUMO
Members of the Friend of GATA (FOG) family of transcriptional co-factors are required for the development of both the cardiovascular and hematopoietic systems. FOG proteins physically interact with members of the GATA family of transcriptional activators and modulate their activity. We have previously shown that FOG-2 can bind to the N-terminal zinc finger of GATA4 and, via this interaction, repress GATA4-mediated transcriptional activation of various cardiac promoters. In this report we further characterize the domain of FOG-2 necessary for repression of GATA4 transcriptional activity. We show that FOG-2-mediated repression is not blocked by the histone deacetylase inhibitor tricostatin A, suggesting that FOG-2 repression of GATA4 occurs via a histone deacetylase independent mechanism. N-terminal deletion mutants of FOG-2 revealed that the first 12 amino acids of FOG-2 are necessary for FOG-2-mediated repression. Fusion of these 12 amino acids to the DNA binding domain of GAL4 demonstrated that this region is sufficient to mediate transcriptional repression even when recruited to a heterologous promoter. Single amino acid substitutions within this N-terminal domain of FOG-2 defined the critical amino acid sequence as RRKQxxPxxI. Interestingly, a search of the NCBI protein data base identified several other partially characterized zinc finger transcriptional repressors from various vertebrate species that contained this motif at their N terminus. Taken together, these observations define a novel transcriptional repression motif and a superfamily of zinc finger transcriptional repressors.