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Romero N.,University of the Republic of Uruguay | Martinez-Acedo P.,Centro Biologia Molecular Severo Ochoa CMB CSIC | Martinez-Ruiz A.,Servicio de Inmunologia | Quijano C.,University of the Republic of Uruguay | And 5 more authors.
Cardiovascular Research | Year: 2010

AimsCyclosporine A (CsA) has represented a fundamental therapeutic weapon in immunosupression for the past three decades. However, its clinical use is not devoid of side effects, among which hypertension and vascular injury represent a major drawback. Endothelial cells are able to generate reactive oxygen and nitrogen species upon exposure to CsA, including formation of peroxynitrite. This may result in endothelial cell toxicity and increased tyrosine nitration. We have now studied the subcellular origin of superoxide formation in endothelial cells treated with CsA and the biochemical consequences for the function of mitochondrial enzymes.Methods and resultsBy using electron spin resonance and endothelial cells lacking functional mitochondria, we showed that superoxide anion is generated in mitochondria. This was associated with an effect of CsA on bioenergetic parameters: increased mitochondrial membrane potential and inhibition of cellular respiration. In addition, CsA inhibited the activity of the mitochondrial enzymes aconitase and manganese superoxide dismutase (MnSOD). The use of murine lung endothelial cells deficient in endothelial nitric oxide synthase (eNOS) and NOS/peroxynitrite inhibitors allowed us to establish that the presence of eNOS and concomitant NO synthesis and peroxynitrite formation were essential for CsA induced nitration and inhibition of MnSOD activity. As the latter has been shown to become inactivated by nitration, we sought to identify this modification by mass spectrometry analysis. We found that CsA induced specific MnSOD tyrosine 34 nitration both in the recombinant protein and in endothelial cells overexpressing MnSOD.ConclusionWe propose that CsA induced endothelial damage may be related to increased mitochondrial superoxide formation and subsequent peroxynitrite-dependent nitroxidative damage, specifically targeting MnSOD. The inactivation of this key antioxidant enzyme by tyrosine nitration represents a pathophysiological cellular mechanism contributing to self-perpetuation and amplification of CsA-related vascular toxicity. © 2010 The Author. Source

Alvarado Cardenas M.,Servicio de Medicina Interna | Marin Sanchez A.,Servicio de Inmunologia | Lima Ruiz J.,Servicio de Medicina Interna
Medicina Clinica | Year: 2015

Statins are the most widely used drugs for both primary and secondary prevention of cardiovascular diseases and those associated with atherosclerosis. About 25 million people are on statin therapy in the world. Although they are well tolerated by most patients and have a safety profile, some patients have muscle level alterations. The biological effects associated with these drugs are known as pleiotropic; they are of such interest and diversity that explains, in part, some of the actions of statins, especially in relation to inflammation and the immune system. Some patients have certain immune disorders that can turn into an undesirable clinical expression. Recent studies have shown that they can trigger autoimmune phenomena. Pathologies have been described in which these agents act as triggers such as immune-mediated necrotizing myopathy or indirectly in dermatomyositis or autoimmune hepatitis, among others. Given the high number of people being treated with statins, we believe that this is a clinically relevant problem and therefore worthy of study. © 2015 Elsevier España, S.L.U. Source

Hamdouch K.,Biotecnologia y Salud Publica | Rodriguez C.,Servicio de Inmunologia | Perez-Venegas J.,Servicio de Reumatologia | Rodriguez I.,Biotecnologia y Salud Publica | And 5 more authors.
Clinica Chimica Acta | Year: 2011

Background: Anticentromere autoantibodies have been reported to be associated with scleroderma and serve as a marker in different rheumatic diseases in humans. Major centromere autoantigens described so far include constitutive kinetochore proteins such as CENPA, CENPB, CENPC and CENPH and facultative proteins such as CENPE, CENPF and INCENP. We examined the inner kinetochore component CENPI as a new putative centromere autoantigen in scleroderma patients. Methods: To test for the presence of CENPI centromere autoantibodies, 72 sera from patients with systemic lupus erythematosus and systemic sclerosis were assayed by immunofluorescence and further tested by immunoblots with an Nt-CENPI recombinant protein. Results: 8 out of 31 (25.8%) patients diagnosed of scleroderma or Undifferentiated Connective Tissue Disease (UCTD) produced anti-CENPI autoantibodies. Epitopes were demonstrated to be located mainly but not exclusively in the N-terminal domain of the human CENPI protein. Five of the 8 (62.5%) CENPI positive sera also had other autoantibodies related to primary biliary cirrhosis. Further, two patients (25%) with anti-CENPI autoantibodies had concurrent diagnosis of primary biliary cirrhosis. Conclusions: This study demonstrates that CENPI, a centromere protein that localizes to the inner kinetochore structure, is a human autoantigen. The significance of anti-CENPI autoantibodies could be relevant in scleroderma patients as a marker for concurrent autoimmune liver disease. © 2011 Elsevier B.V. Source

Comabella M.,Hospital Universitari Vall dHebron | Caminero A.B.,Hospital Universitari Vall dHebron | Malhotra S.,Hospital Universitari Vall dHebron | Agullo L.,Hospital Universitari Vall dHebron | And 12 more authors.
Neurology | Year: 2013

Objectives: To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution-R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease. Methods: The effects of rs1800693 and rs4149584 on 2 measures of disease severity, age at disease onset and Multiple Sclerosis Severity Score, were analyzed in 2,032 patients with MS. In a subgroup of patients, serum levels of the soluble form of TNF-R1 (sTNF-R1) were measured by ELISA; mRNA expression levels of the full-length TNF-R1 and A6-TNF-R1 isoform were investigated in peripheral blood mononuclear cells (PBMC) by real-time PCR; cell surface expression of the TNF-R1 was determined in T cells by flow cytometry. Results: For rs4149584, R92Q carriers were younger at disease onset and progressed slower compared to noncarriers. However, no association with disease severity was observed for rs1800693. Serum levels of sTNF-R1 and mRNA expression levels of the full-length receptor were significantly increased in patients with MS carrying the R92Q mutation (p = 0.003 and p = 0.011, respectively), but similarly distributed among rs1800693 genotypes; cell surface TNF-R1 expression in T cells did not differ between rs4149584 and rs1800693 genotypes. The truncated soluble A6-TNF-R1 isoform was identified in PBMC from patients carrying the risk allele for rs1800693. Conclusions: These findings suggest that both rs1800693 and rs4149584 TNFRSF1A polymorphisms have functional consequences in the TNF-R1. © 2013 American Academy of Neurology. Source

Palazon A.,University of Navarra | Martinez-Forero I.,University of Navarra | Teijeira A.,University of Navarra | Morales-Kastresana A.,University of Navarra | And 10 more authors.
Cancer Discovery | Year: 2012

The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confi rmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infi ltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α- knockout T cells, and such HIF-1α-defi cient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infi ltrating and co-transferred HIF-1α-suffi cient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confi ne the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver infl ammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade. SIGNIFICANCE: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1α system increases expression of CD137 on tumor-infi ltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. © 2012 American Association for Cancer Research. Source

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