Padron RI. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling. Am J Physiol Heart Circ Physiol 306: H641-H653, 2014. First published January 10, 2014; doi:10.1152/ajpheart.00641.2013.-Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-␥ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation. inflammation; vascular injury; aging; neointima; vascular smooth muscle cells AGING IS RECOGNIZED AS A MAJOR and independent risk factor for the development of vascular restenosis (29). This risk can be explained by profound, age-dependent changes in vascular structure and physiology that lead to endothelial dysfunction (18) and a chronic inflammatory stage (53), which impair healing and render a vascular system prone to develop occlusive neointimas in response to injury. However, even when this notion is largely accepted, the mechanisms by which aging alters vascular physiology and repair have remained understudied to date.The process of aging increases and sustains inflammation within the vascular wall (52). Macrophages are commonly recognized as the most important cell type in the chronicity of this process (37). Indeed, inflammation in arteries of aged individuals is evidenced by an excessive accumulation of macrophages in the inner layer of the arterial wall (intima), and this occurs in the presence o...
Systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are autoimmune illnesses characterized by the presence of high titers of autoantibodies directed against a wide range of ‘self ’ antigens. Proteins of the U1 small nuclear ribonucleoprotein particle (U1 snRNP) are among the most immunogenic molecules in patients with SLE and MCTD. The recent release of a crystallized U1 snRNP provides a unique opportunity to evaluate the effects of tertiary and quaternary structures on autoantigenicity within the U1 snRNP. In the present study, an epitope map was created using the U1 snRNP crystal structure. A total of 15 peptides were tested in a cohort of 68 patients with SLE, 29 with MCTD and 26 healthy individuals and mapped onto the U1 snRNP structure. Antigenic sites were detected in a variety of structures and appear to include RNA binding domains, but mostly exclude regions necessary for protein–protein interactions. These data suggest that while some autoantibodies may target U1 snRNP proteins as monomers or apoptosis-induced, protease-digested fragments, others may recognize epitopes on assembled protein subcomplexes of the U1 snRNP. Although nearly all of the peptides are strong predictors of autoimmune illness, none were successful at distinguishing between SLE and MCTD. The antigenicity of some peptides significantly correlated with several clinical symptoms. This investigation implicitly highlights the complexities of autoimmune epitopes, and autoimmune illnesses in general, and demonstrates the variability of antigens in patient populations, all of which contribute to difficult clinical diagnoses.
The spliceosome is a dynamic, macromolecular complex, which removes non-protein-coding introns from pre-mRNA to form mature mRNA in a process known as splicing. This ribonucleoprotein assembly is comprised of five uridine-rich small nuclear RNAs (snRNAs) as well as over 300 proteins. In humans, several of the known proteinaceous splicing factors are members of the immunophilin superfamily. Immunophilins are peptidylprolyl cis-trans isomerases that catalyze the conversion of proteins from cis to trans at Xaa-Pro bonds. Our review of the data indicates that some members of this protein family are activators of spliceosomal proteins by way of folding and transport.
Background The role of immune cells in arteriovenous fistulae (AVF) maturation is poorly understood and has received, until quite recently, little attention. This study examines the role of T lymphocytes in AVF vascular remodeling. Methods Experimental fistulae were created in athymic rnu nude rats lacking mature T lymphocytes and euthymic control animals by anastomosing the left superior epigastric vein to the nearby femoral artery. Blood flow rates, wall morphology and histological changes were assessed in AVF 21 days after creation. The effect of CD4+ lymphocytes on AVF maturation in athymic animals was analyzed by adoptive transfer of cells after fistula creation. Results The absence of T lymphocytes compromised blood flow in experimental fistulae. Histopathological inspection of AVF from athymic rats revealed that T cell immunodeficiency negatively affected venous vascular remodeling, as evidenced by a reduced lumen, a thick muscular layer and a low number of inflammatory cells compared to control animals. Adoptive transfer of CD4+ lymphocytes from euthymic rats into athymic animals before and after fistula creation improved blood flow and reduced intima-media thickness. Conclusion These results point at the protective role of CD4+ lymphocytes in the remodeling of the AVF vascular wall.
The spliceosome is a high molecular weight cellular complex responsible for the removal of non‐protein coding introns from pre‐mRNA to form mature mRNA transcripts. It comprises five major uridine (U)‐rich small nuclear (sn)RNAs, to which a number of proteins bind and interact. Variant snRNAs have been identified in several organisms, although it remains to be seen whether or not these isoforms have distinct cellular roles. Nevertheless, many of these sequences have spatio‐temporal trends in expression, suggesting that the variant snRNAs are not functionally equivalent. In this report, we examine and contrast the available data on snRNAs in two strains of Bombyx mori: European 703 and Nistari from India. In addition, the genomic snRNA sequences from the p50T strain are described. Thus far, isoforms of U1, U2, U4 and U6 have been characterized in B. mori European 703 and/or Nistari strains using expression libraries. In this study, an in silico approach was used to identify the genomic counterparts of the U snRNA variants in the 6X Whole Genome Shotgun (WGS) of the B. mori p50T strain. The present study is the first comparison of snRNAs in different B. mori strains. Overall, we found that 46 full length U snRNA loci and 76 suspected truncated genes are present in the B. mori genome of the p50T strain. A total of 14 full length genes match previously identified snRNAs in either the Nistari and/or the European 703 strains. Multiple sequence alignments of upstream controlling elements revealed conserved boxes in a subset of U snRNA genes. The presence of divergent promoters within specific snRNA 5′‐flanking sequences suggests that these loci may be transcribed from different controlling elements or are not expressed. The number of nucleotide differences within a given type of U snRNA is strongly correlated with its copy number in the genome (r2 = 77.8%) and it may reflect a relaxation of selection pressure on genes of higher copy number. The multiplicity in gene copy may provide for numerous, full length snRNA loci with variable sequences that adopt unique roles in pre‐mRNA splicing, possibly by modulating protein–RNA and/or RNA–RNA interactions and in doing so affecting gene expression and development.
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