Microparticle release in remote ischemic conditioning mechanism

Remote ischemic conditioning (RCond) induced by short periods of ischemia and reperfusion of an organ or tissue before myocardial reperfusion is an attractive strategy of cardioprotection in the context of acute myocardial infarction. Nonetheless, its mechanism remains unknown. A humoral factor appears to be involved, although its identity is currently unknown. We hypothesized that the circulating microparticles (MPs) are the link between the remote tissue and the heart. MPs from rats and healthy humans undergoing RCond were characterized. In rats, RCond was induced by 10 min of limb ischemia. In humans, RCond was induced by three cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff. In the second part of the study, rats underwent 40 min myocardial ischemia followed by 2 h reperfusion. Infarct size was measured and compared among three groups of rats: 1) myocardial infarction alone (MI) (n = 6); 2) MI + RCond started 20 min after coronary ligation (n = 6); and 3) MI + injection of RCond-derived rat MPs (MI + MPs) (n = 5). MPs from endothelial cells (CD54(+) and CD146(+) for rats and humans, respectively) and procoagulant MPs (Annexin V(+)) markedly increased after RCond, both in rats and humans. RCond reduced infarct size (24.4 ± 5.9% in MI + RCond vs. 54.6 ± 4.7% in MI alone; P < 0.01). Infarct size did not decrease in MI + MPs compared with MI alone (50.2 ± 6.4% vs. 54.6 ± 4.7%, not significantly different). RCond increased endothelium-derived and procoagulant MPs in both rats and humans. However, MP release did not appear to be a biological vector of RCond in our model

Nocturnal release of leukocyte-derived microparticles in males with obstructive sleep apnoea

Multiple pathophysiological mechanisms have been proposed to contribute to the increased cardiovascular morbidity in obstructive sleep apnoea (OSA), including autonomic dysfunction, inflammation, oxidative stress and endothelial dysfunction 1. Microparticles (MPs) are small membrane vesicles that are shed from circulating cells or from the components of the vessel wall in response to activation and apoptosis. There is growing evidence in support of a potential role of MPs in the field of cardiovascular diseases. Increased levels of MPs derived from various cell types are found in patients at risk of cardiovascular diseases 2. By modulating inflammation, coagulation, vasomotor reactivity and angiogenesis, MPs might directly contribute to cardiovascular diseases 2. Recent case–control studies suggest a potential involvement of MPs in OSA-associated cardiovascular morbidity 3–6. An increase in morning levels of MPs derived from activated leukocytes has been demonstrated in otherwise healthy male OSA patients with marked nocturnal desaturations 5. In vitro, nitric oxide (NO) production by endothelial cells incubated with MPs from OSA patients correlates negatively with circulating levels of activated leukocyte-derived MPs 5. Ex vivo, mice previously injected with MPs from OSA patients display endothelial dysfunction, reduced endothelial NO release and increased adhesion molecule expression 5

Circulating microparticles from patients with obstructive sleep apnea enhance vascular contraction: mandatory role of the endothelium

Obstructive sleep apnea (OSA) is characterized by repetitive apnea-hypopnea cycles during sleep associated with oxygen desaturation and sleep disruption. We evaluated the role of circulating microparticles (MPs) from patients with OSA in the regulation of vascular function. MPs from whole blood from patients with OSA or control subjects were injected i.v. into mice. Injection of MPs from patients with OSA induced ex vivo vascular hyperreactivity in aortas with functional endothelium but, in contrast, hyporeactivity in vessels without functional endothelium. Vascular hyperreactivity was blunted in the presence of a nitric oxide synthase inhibitor alone or combined with the cyclooxygenase inhibitor indomethacin. MPs from patients with OSA reduced endothelial nitric oxide synthase activity and nitric oxide production, increased aortic cyclooxygenase-1 and cyclooxygenase-2 expression, and increased thromboxane A(2) and prostacyclin production. Blockade of thromboxane A(2) receptor did not affect the serotonin response in arteries from OSA MP-treated mice. A superoxide dismutase mimetic reduced the vascular hyperreactivity induced by MPs from patients with OSA but had no effect on contraction in vessels from control and non-OSA MP-treated mice. These data provide evidence that circulating MPs from patients with OSA induce ex vivo vascular hyperreactivity with the obligatory role of the endothelium and subtle interactions between the nitric oxide and cyclooxygenase pathways and metabolites. These results highlight the participation of MPs in vascular dysfunction associated with OSA

Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity via Fas/Fas-ligand pathway in mice

Peer reviewedPublisher PD

Living in several languages: Language, gender and identities

Living in several languages encompasses experiencing and constructing oneself differently in each language. The research study on which this article is based takes an intersectional approach to explore insider accounts of the place of language speaking in individuals’ constructions of self, family relationships and the wider context. Twenty-four research interviews and five published autobiographies were analysed using grounded theory, narrative and discursive analysis. A major finding was that learning a new language inducted individuals into somewhat ‘stereotyped’ gendered discourses and power relations within the new language, while also enabling them to view themselves differently in the context of their first language. This embodied process could be challenging and often required reflection and discursive work to negotiate the dissimilarities, discontinuities and contradictions between languages and cultures. However, the participants generally claimed that their linguistic multiplicity generated creativity. Women and men used their language differences differently to ‘perform their gender’. This was particularly evident in language use within families, which involved gendered differences in the choice of language for parenting – despite the fact that both men and women experience their first languages as conveying intimacy in their relationships with their children. The article argues that the notion of ‘mother tongue’ (rather than ‘first language’) is unhelpful in this process as well as in considering the implications of living in several languages for systemic therapy

Transport of small anionic and neutral solutes through chitosan membranes: Dependence on cross-linking and chelation of divalent cations

Chitosan membranes were prepared by solvent casting and cross-linked with glutaraldehyde at several ratios under homogeneous conditions. The cross-linking degree, varying from 0 to 20%, is defined as the ratio between the total aldehyde groups and the amine groups of chitosan. Permeability experiments were conducted using a side-by-side diffusion cell to determine the flux of small molecules of similar size but with different chemical moieties, either ionized (benzoic acid, salicylic acid, and phthalic acid) or neutral (2-phenylethanol) at physiological pH. The permeability of the different model molecules revealed to be dependent on the affinity of those structurally similar molecules to chitosan. The permeability of the salicylate anion was significantly enhanced by the presence of metal cations commonly present in biological fluids, such as calcium and magnesium, but remained unchanged for the neutral 2-phenylethanol. This effect could be explained by the chelation of metal cations on the amine groups of chitosan, which increased the partition coefficient. The cross-linking degree was also correlated with the permeability and partition coefficient. The change in the permeation properties of chitosan to anionic solutes in the presence of these metallic cations is an important result and should be taken into consideration when trying to make in vitro predictions of the drug release from chitosan-based controlled release systems

Mice lacking endoglin in macrophages show an impaired immune response

24 p.-9 fig.-1 tab. Ojeda Fernández, Luisa et al.Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-OslerWeber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Engfl/flLysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Engfl/flLysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.This work was funded by: Ministerio de Economía y Competitividad of Spain (SAF2011-23475 to LMB; SAF2013-43421-R and SAF2010- 19222 to CB.Peer reviewe

Targeting RNA adenosine editing and modification enzymes for RNA therapeutics

\ua9 2025 The Author(s)Adenosine-to-inosine (A-to-I) RNA editing, and N6 methyladenosine (m6A) are among the most abundant modifications in eukaryotic messenger RNA, affecting various aspects of RNA metabolism and cellular function, including proliferation, differentiation, responses to stressors, and cell death. Recent preclinical evidence suggests that both modifications play a significant role in multiple disorders, including infections, chronic inflammatory diseases, and cancer, sparking great interest in their therapeutic potential. Structural characterization of ADARs (adenosine deaminases acting on RNA) and key m6A enzymes has enabled the development of small molecule inhibitors modulating their expression, enzymatic activity, or binding to target RNAs. Herein, we review preclinical evidence supporting the therapeutic benefits of targeting ADARs and m6A enzymes in diverse disease contexts. Small molecule inhibitors of RNA modification enzymes have shown potent anti-proliferative and pro-apoptotic effects in cancer cells, and have successfully inhibited tumor growth in vivo, without evident toxicity, while their combination with immuno-/chemotherapeutics displayed synergistic anti-neoplastic action. Adenosine RNA editing via recruitment of endogenous ADARs and usage of guide RNAs showed remarkable efficacy in correcting G-to-A point mutations and restoring the associated protein expression with limited off-target activity. Future studies are warranted to evaluate the safety and clinical efficacy of RNA editing or modification-targeting therapeutics in patients

Loss of endothelial endoglin promotes high-output heart failure through peripheral arteriovenous shunting driven by VEGF signaling

Rationale: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. Objective: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. Methods and Results: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis—a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. Conclusions: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber—an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function