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Background and purpose: Persistent endoplasmic reticulum (ER) stress and its deleterious crosstalk with mitochondria trigger oxidative stress, mitochondrial dysfunction and inflammation contributing to the pathophysiology of a myriad of cardiovascular diseases linked with hypertension such as abdominal aortic aneurysm (AAA) and cardiac hypertrophy. The purpose of this work was to determine whether inhibition of ER and mitochondrial stress is effective preventing aneurysm development and cardiac hypertrophy in angiotensin II (AngII)-infused apolipoprotein-E-deficient (ApoE−/−) mice. Experimental approach and results: The expression of ER stress markers (Hspa5, Atf4, Atf6, Chop and Ern1) was up-regulated in aneurysmal abdominal aortas from AngII-infused ApoE−/−mice. The treatment with ER stress inhibitors improved survival, decreased systolic blood pressure, limited the incidence and severity of AAA and reduced the AngII-induced increase of aortic diameter evaluated by ultrasonography. These beneficial effects were mimicked by the mitochondria-targeted tetrapeptide SS31. The disorganisation of elastin and collagen fibres, the increased expression of metalloproteinases and pro-inflammatory markers and the infiltration of immune cells induced by AngII in the abdominal aorta were effectively reduced by both, ER inhibitors and SS31. Additionally, treatment with SS31 prevented the alteration of mitochondrial dysfunction and reduced ER stress markers expression and plasmatic ROS levels. Mechanistically, CHOP deficiency in ApoE−/−mice reduced the blood pressure and the incidence of AAA. Interestingly, both pharmacological interventions and CHOP deficiency attenuated AngII-induced cardiac hypertrophic remodelling and improved systolic and diastolic function. Conclusions: Our data evidence that inhibition of ER and mitochondrial stress limits abdominal aortic aneurysm formation, increases survival and ameliorates hypertensive cardiac hypertrophy.

Abdominal aortic aneurysm (AAA) is increasing due to aging of the population and is a major cause of death among the elderly. Ultrasound screening programs are useful in early diagnosis, but aneurysm size is not always a good predictor of rupture. Our aim was to analyze the value of circulating molecules related to oxidative stress and inflammation as new biomarkers to assist the management of AAA. The markers were quantified by ELISA, and their expression in the aneurysmal wall was studied by real-time PCR and by immunostaining. Correlation analysis of the studied markers with aneurysm diameter and peak wall stress (PWS), obtained by finite element analysis, and multivariate regression analysis to assess potential confounding factors were performed. Our study shows an extensive inflammatory infiltration in the aneurysmal wall, mainly composed by T-cells, macrophages and B-cells and altered levels of reactive oxygen species (ROS), IgM, IgG, CD38, GDF15, S100A4 and CD36 in plasma and in the aneurysmal tissue of AAA patients compared with controls. Circulating levels of IgG, CD38 and GDF15 positively correlated with abdominal aortic diameter, and CD38 was correlated with PWS. Our data show that altered levels of IgG, CD38 and GDF15 have potential diagnostic value in the assessment of AAA., This work was funded by grants from the Spanish Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) (grants PI17/01837 to M.G.; PI17/01455 to D.S. and PI18/00919 to C.R. and M.C.) and by CIBER on Cardiovascular Diseases (CIBERCV, CB16/11/00257), an initiative from ISCIII. The study was co-founded by Fondo Europeo de Desarrollo Regional (FEDER), a way to make Europe M.N. is supported by BHF (PG17/73/33251).

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer.In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers.Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease., This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) [grant numbers CP15/00126, PI17/08137 (to M.G.), PI18/0919 (to C.R.) and RTI2018-094727-B-100 (to J.M.G.)]; the CIBERCV [grant number CB16/11/00257]; the ISCIII, Miguel Servet I program (grant number CP15/00126 (to M.N.M. and M.G.)]; and by Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR; program of support to Research Groups. Ref. 2017-SGR-00333). The study was co-founded by Fondo Europeo de Desarrollo Regional (FEDER)-The way to build Europe

Marfan syndrome (MFS) is caused by mutations in the protein fibrillin-1 (FBN1) which affects the integrity of connective tissue elastic fibres. The most severe clinical outcome is the formation of ascending aortic aneurysms. FBN1 mutations are extremely variable and the prediction of disease phenotype and aortic risk is challenging under the prevailing mutation type classification. Finding a better correlation between mutation type and disease development is crucial for patient treatment. By mRNA sequencing of cultured vascular smooth muscle cells derived from control subjects and from the dilated and non-dilated aortic tunica media of MFS patients, we found a scarcely described FBN1 3'UTR mutation. This mutation was accompanied by a clear gene ontological endoplasmic reticulum (ER) stress response in the non-dilated aortic zone, which was confirmed by the increased transcriptional expression of MANF, HSPA5, SEL1L, DDIT3/CHOP and CRELD2 as well as protein expression levels of BiP/GRP78, CHOP and sXBP1. Moreover, the ER stress response was accompanied by a decrease in the phosphorylation levels of the protein translation regulator elF2α. In conclusion, we here identify a 3'UTR mutation of FBN1 in MFS patients, whose molecular mechanism suggest the involvement of the ER stress response in the formation of the aortic aneurysm. Our results emphasise the importance of mutations in non-coding regions and their resulting molecular mechanisms in the development of connective tissue diseases with impact on the cardiovascular system. This work was supported by grants to G.E. (SAF 2015-64136-R and SAF 2017-80309-R). M.G. is supported by the Miguel Servet Program (ISCIII; CP15/00126). The support of the NMF to GE is acknowledge.

Introduction Antibodies targeting the inward-rectifying potassium channel KIR4.1 have been associated with multiple sclerosis (MS) but studies using diverse techniques have failed to replicate this association. The detection of these antibodies is challenging; KIR4.1 glycosylation patterns and the use of diverse technical approaches may account for the disparity of results. We aimed to replicate the association using three different approaches to overcome the technical limitations of a single technique. We also performed a systematic review to examine the association of anti-KIR4.1 antibodies with MS. Methods Serum samples from patients with MS (n = 108) and controls (n = 77) were tested for the presence of anti-KIR4.1 antibodies using three methods: 1) by ELISA with the low-glycosylated fraction of recombinant KIR4.1 purified from transfected HEK293 cells according to original protocols; 2) by immunocytochemistry using KIR4.1-transfected HEK293 cells; and 3) by immunocytochemistry using the KIR4.1.-transfected MO3.13 oligodendrocyte cell line. We developed a systematic review and meta-analysis of the association of anti-KIR4.1 antibodies with MS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results We did not detect anti-KIR4.1 antibodies in the MS patients or in controls using ELISA. Neither did we detect any significant reactivity against the antigen on the cell surface using the KIR4.1-transfected HEK293 cells or the KIR4.1-transfected MO3.13 cells. We included 13 prospective controlled studies in the systematic review. Only three studies showed a positive association between anti-KIR4.1 and MS. Clinical and statistical heterogeneity between studies precluded meta-analysis of their results. Conclusion We found no association between anti-KIR4.1 antibody positivity and MS. Although this lack of replication may be due to technical limitations, evidence from our study and others is mounting against the role of KIR4.1 as a relevant MS autoantigen.