28 research outputs found

    Pathophysiology of Atherosclerosis

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    Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. This review focuses on the different stages of atherosclerosis development, ranging from endothelial dysfunction to plaque rupture. In addition, the post-transcriptional regulation and modulation of atheroma plaque by microRNAs and lncRNAs, the role of microbiota, and the importance of sex as a crucial risk factor in atherosclerosis are covered here in order to provide a global view of the disease.This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). A.B.-V. was supported by Programa de especialización de Personal Investigador Doctor en la UPV/EHU (2019) 2019/2020; U.G-G. was supported by Margarita Salas Grant; and S.J. and A.L-S were supported by a grant PIF (2017–2018) and PIF (2019–2020) Gobierno Vasco, respectively

    Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

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    Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). U.G.-G. was supported by Fundación Biofísica Bizkaia. A.B.-V. was supported by Programa de especialización de Personal Investigador Doctor en la UPV/EHU (2019) 2019–2020. S.J. and A.L.-S. were supported by a grant PIF (2017–2018) and (2019–2020), Gobierno Vasco, respectively. A.L.-S. was partially supported by Fundación Biofísica Bizkaia

    Replacement of Cysteine at Position 46 in the First Cysteine-Rich Repeat of the LDL Receptor

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    Background and aims Pathogenic mutations in the Low Density Lipoprotein Receptor gene (LDLR) cause Familial Hypercholesterolemia (FH), one of the most common genetic disorders with a prevalence as high as 1 in 200 in some populations. FH is an autosomal dominant disorder of lipoprotein metabolism characterized by high blood cholesterol levels, deposits of cholesterol in peripheral tissues such as tendon xanthomas and accelerated atherosclerosis. To date, 2500 LDLRvariants have been identified in the LDLR gene; however, only a minority of them have been experimentally characterized and proven to be pathogenic. Here we investigated the role of Cys46 located in the first repeat of the LDL receptor binding domain in recognition of apolipoproteins. Methods Activity of the p.(Cys46Gly) LDLR variant was assessed by immunoblotting and flow cytometry in CHO-/d/A7 expressing the receptor variant. Affinity of p.(Cys46Gly) for LDL and VLDL was determined by solid-phase immunoassays and in silico analysis was used to predict mutation effects. Results and conclusion Functional characterization of p.(Cys46Gly) LDLRvariant showed impaired LDL and VLDL binding and uptake activity. Consistent with this, solid-phase immunoassays showed the p. (Cys46Gly) LDLR variant has decreased binding affinity for apolipoproteins. These results indicate the important role of Cys46 in LDL receptor activity and highlight the role of LR1 in LDLr activity modulation. This study reinforces the significance of in vitro functional characterization of LDL receptor activity in developing an accurate approach to FH genetic diagnosis. This is of particular importance because it enables clinicians to tailor personalized treatments for patients' mutation profile.Progenika Biopharma SA, is an Spanish biotech company founded in 2000 with headquarters in Derio, Bizkaia (SPAIN). Progenika Biopharma SA did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries to M.S. and L.P. This work was supported by Gobernio Vasco, ELKARTEK BIOGUNE 2015 (Codigo KK-2015/0000089) and Basque Government (Grupos Consolidados IT849-13). A. B-V. was supported by a grant (PIF 2014/2015) Eusko Jaurlaritza and S.J. was supported by grant (PIF 2018/2019) Eusko Jaurlaritza. The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

    Towards a new generation of non-cytotoxic shape memory thermoplastic polyurethanes for biomedical applications

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    In recent decades, the technology of polymeric materials used in biomedical applications has been greatly improved, replacing the metals that had been used until now. This change has not only meant an improvement in the cost of the raw material and in its processing, but it is also due to the fact that there are applications, such as stents, where the material is required to have a certain flexibility, both during the surgical intervention and during the healing or conditioning the tissue in which the intervention is performed. In this type of application, the so-called shape memory polymers (SMPs) are very interesting, but for this, they must meet the condition of being biocompatible. In this work, new polyurethane materials have been designed in which, in addition to shape memory prevailing, adequate cell proliferation values are obtained for possible use in biomedical applications. Furthermore, during the synthesis, in order to avoid undesired and toxics subproducts, instead of the typical aromatic diisocyanates, an aliphatic 1,6-hexamethylene diisocyanate (HDI) has been selected. Moreover, neither solvents nor catalysts were used, which makes eco-friendly synthesis suitable for scaling at an industrial level. Finally, castor oil (CO) has been used as one of the main synthesis reagents, which is an abundant compound obtained from biological sources. For all this, it can be concluded that the polymers described here have a wide range of application possibilities (biomedicine, food packaging…), and are highly interesting to preserve our Planet.Authors would like to acknowledge the Basque Government funding within the ELKARTEK 2020 AVANSITE (KK-2020/00019). Also, authors gratefully acknowledge funding from the University of the Basque Country (GIU20/075). The authors thank for technical and human support provided by SGIker (UPV/EHU/ ERDF, EU)

    miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression

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    Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance.This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). A.B.-V. was supported by Programa de especialización de Personal Investigador Doctor en la UPV/EHU (2019) 2019-2020. U.G-G. was supported by Fundación Biofísica Bizkaia. S.J. was supported by a grant PIF (2017–2018), Gobierno Vasco. We sincerely thank Haziq Siddiqi (Harvard Medical School) for his critical reading and editing of this manuscript

    Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

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    15 pags, 8 figs, 1 tab. -- This article contains supplementary material (Table S1, Figs. S1–S4, and Data Sets S1–S4.1)The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O-glycan sites. Moreover, we found that O-glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11–mediated O-glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O-glycosylation of LDLR-related proteins and identified conserved O-glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11–mediated LDLR and VLDLR O-glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O-glycosylation increased affinity for LDL by 5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease.This work was supported by the Læge Sofus Carl Emil Friis og hustru Olga Doris Friis’ Legat, the Kirsten og Freddy Johansen Fonden, the Lundbeck Foundation, the A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til Almene Formaal, the Mizutani Foundation, the Novo Nordisk Foundation, the Danish Research Council Sapere Aude Research Talent Grant (to K. T. S.), and the Danish National Research Foundation (DNRF107). The authors declare that they have no conflicts of interest with the contents of this articl