Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a ...breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA. The intraluminal thrombus exerts its pathogenic effect through platelet activation, fibrin formation, binding of plasminogen and its activators, and trapping of erythrocytes and neutrophils, leading to oxidative and proteolytic injury of the arterial wall. These events occur mainly at the intraluminal thrombus-circulating blood interface, and pathological mediators are conveyed outwards, where they promote matrix degradation of the arterial wall. In response, neo-angiogenesis, phagocytosis by mononuclear cells, and a shift from innate to adaptive immunity in the adventitia are observed. Abdominal aortic aneurysm thus represents an accessible spatiotemporal model of human atherothrombotic progression towards clinical events, the study of which should allow further understanding of its pathogenesis and the translation of pathogenic biological activities into diagnostic and therapeutic applications.
As the main particulate component of the circulating blood, RBCs play major roles in physiological hemodynamics and impact all arterial wall pathologies. RBCs are the main determinant of blood ...viscosity, defining the frictional forces exerted by the blood on the arterial wall. This function is used in phylogeny and ontogeny of the cardiovascular (CV) system, allowing the acquisition of vasomotricity adapted to local metabolic demands, and systemic arterial pressure after birth. In pathology, RBCs collide with the arterial wall, inducing both local retention of their membranous lipids and local hemolysis, releasing heme-Fe
with a high toxicity for arterial cells: endothelial and smooth muscle cells (SMCs) cardiomyocytes, neurons, etc. Specifically, overloading of cells by Fe
promotes cell death. This local hemolysis is an event associated with early and advanced stages of human atherosclerosis. Similarly, the permanent renewal of mural RBC clotting is the major support of oxidation in abdominal aortic aneurysm. In parallel, calcifications promote intramural hemorrhages, and hemorrhages promote an osteoblastic phenotypic shift of arterial wall cells. Different plasma or tissue systems are able, at least in part, to limit this injury by acting at the different levels of this system.
Aims
There are controversial data on the ability of the components of mineral metabolism (vitamin D, phosphate, parathormone PTH, fibroblast growth factor‐23 FGF23, and klotho) to predict ...cardiovascular events. In addition, it is unknown whether they add any prognostic value to other well‐known biomarkers.
Methods and results
In 969 stable coronary patients, we determined plasma levels of all the aforementioned components of mineral metabolism with a complete set of clinical and biochemical variables, including N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), high‐sensitivity troponin I (hs‐TnI), and high‐sensitivity C‐reactive protein. Secondary outcomes were ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and heart failure or death. The primary outcome was a composite of the secondary outcomes. Median follow‐up was 5.39 years. Age was 60 (52–72) years. Median glomerular filtration rate was 80.4 (65.3–93.1) mL/min/1.73 m2. One‐hundred and eighty‐five patients developed the primary outcome. FGF23, PTH, hs‐TnI, and NT‐proBNP were directly related with the primary outcome on univariate Cox analysis, while Klotho and calcidiol were inversely related. On multivariate analysis, only PTH (HR 1.058 CI 1.021–1.097; P = 0.002) and NT‐proBNP (HR 1.020 CI 1.012–1.028; P < 0.001) were independent predictors of the primary outcome but also for the secondary outcome of heart failure or death (HR 1.066 CI 1.016–1.119; P = 0.009 and HR 1.024 CI 1.014–1.034; P < 0.001, respectively). PTH was the only biomarker that predicted ischaemic events (HR 1.052 1.010–1.096; P = 0.016). Patients were divided in two subgroups according to FGF23 plasma levels. PTH retained its prognostic value only in patients with FGF23 levels above the median (>85.5 RU/mL) (P < 0.001) but not in patients with low FGF23 levels (P = 0.551). There was a significant interaction between FGF23 and PTH (P = 0.002). However, there was no significant interaction between PTH and both klotho and calcidiol levels.
Conclusions
Parathormone is an independent predictor of cardiovascular events in coronary patients, adding complimentary prognostic information to NT‐proBNP plasma levels. This predictive value is restricted to patients with high FGF23 plasma levels. This should be considered in the design of future studies in this field.
Extensive research has focused on the identification of novel plasma biomarkers to improve our ability to predict cardiovascular events in atherothrombosis. However, classical techniques can only ...assess a limited number of proteins at a time. Given that plasma contains more than 900,000 proteins, this approach will be extremely time-consuming. Novel proteomic approaches make it possible to compare the expression of hundreds of proteins in several samples in a single experiment. The classical approach consists of separation of proteins on a 2-dimensional gel followed by protein identification with mass spectrometry, although new complementary gel-free techniques are emerging. We can thus compare protein expression in an atherosclerotic plaque with that in a normal artery or study plasma proteins in patients with atherothrombosis as compared with healthy subjects. For such approaches, it is not necessary to study the published data to select potential biomarkers. However, because the number of patients that can be studied with most of these techniques is limited, what is really important is the design of the studies, assessing carefully what kind of patients should be included to obtain valid conclusions. Clinicians should thus play a key role in this design along with the basic scientist. In this article, we review several proteomic strategies carried out by our group and others, and we make a call for collaboration between clinicians and experts in proteomics. This collaboration could greatly increase the likelihood of identifying new prognostic biomarker panels in atherothrombosis and other cardiovascular disorders.
The interaction between TNF-like weak inducer of apoptosis (TWEAK, Tnfsf12) and the receptor, fibroblast growth factor-inducible 14 (Fn14), regulates vascular damage through different mechanisms, ...including inflammation. Oxidative stress plays a major role in inflammation and the development of atherosclerosis, but the relationship between TWEAK and oxidative stress is, however, poorly understood.
In this study, we found that TWEAK and Fn14 are co-localized with the NADPH subunits, p22phox and Nox2, in human advanced atherosclerotic plaques. Using primary human macrophages and a murine macrophage cell line, we demonstrate that TWEAK promotes ROS production and enhances NADPH oxidase activity. Hence, we show a direct involvement of the TWEAK-Fn14 axis in oxidative stress, as genetic silencing of Fn14 or Nox2 abrogates the TWEAK-induced ROS production. Furthermore, our results point at Rac1 as an upstream mediator of TWEAK during oxidative stress. Finally, using an in vivo murine model we confirmed the major role of TWEAK in oxidative stress, as genetic silencing of Tnfsf12 in an ApoE(-/-) background reduces the number of DHE and 8-hydroxydeoxyguanosine-positive macrophages by 50%.
Our results suggest that TWEAK regulates vascular damage by stimulating ROS production in an Nox2-dependent manner. These new insights into the TWEAK/Fn14 axis underline their potential use as therapeutic targets in atherosclerosis.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate ...apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice.
ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion.
Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with hyperlipidemia.
Low back pain is a common condition that becomes even more prevalent with aging. A non-pharmacological multidisciplinary approach for chronic non-specific low back pain (CNSLBP) has been recommended, ...but integrating different healthcare professionals is challenging. A multidisciplinary group videoconferencing approach (MGVA) can be helpful. Our aim was to provide evidence on MGVA's feasibility in managing CNSLBP and its impact on clinical practice.
We conducted an open-label, randomized, controlled, parallel-group pilot clinical trial with CNSLBP patients irresponsive to conservative treatment. Patients between 18 and 67 years of age were randomly assigned (1:1) to either Standard-of-Care + MGVA (experimental group) or Standard-of-Care alone (control group). MGVA consisted of integrated sessions for physical rehabilitation/physiotherapy, psychology, and social work treatments. The control group received standard clinical practice treatment. The feasibility was assessed by the number of study procedures completed to at least 80% as planned. The impact on clinical practice was evaluated by the number of patients who changed their status from "candidate" to "non-candidate" to low back surgery as the treatment of choice for CNSLBP. The SF-36, Oswestry Disability Index, and TMMS-24 questionnaires were used. We performed a whole population-based descriptive analysis.
We included 20 patients, but only 18 were randomized (2 withdrew consent before randomization). The mean (SD) age was 53.1 (5.9) years, and mostly women (13/18); 7 were actively employed. In the experimental group, 6/9 (67%, 95%CI:35-88%) patients attended at least 80% of the scheduled procedures, while in the control group, 8/9 (89%, 95%CI:57-98%) did. Additionally, 1 out of 4 (25%) patients in the experimental group changed their status from "candidate" for low back surgery to "non-candidate". None of the 2 patients in the control group did so. We found differences between groups in the SF-36 mental health component (p-value:0.061), Oswestry Disability Index (p-value:0.032), and TMMS-24 Repair component (p-value:0.014) at the end of the trial favoring MGVA.
The multidisciplinary group videoconferencing approach to managing chronic non-specific low back pain was feasible, suggesting overall beneficial effects on patients' health and could play a role in changing a patient's status from "candidate" to "non-candidate" for surgery.
NCT05093543 (ClinicalTrials.gov), first registered in 26/10/2021.
To assess the potential association between TRX-1/PRX-1 and NADPH oxidase (Nox) activity in vivo and in vitro, TRX-1/PRX-1 levels were assessed by ELISA in 84 asymptomatic subjects with known ...phagocytic NADPH oxidase activity and carotid intima-media thickness (IMT). We found a positive correlation between TRX-1/PRX-1 and NADPH oxidase-dependent superoxide production (r=0.48 and 0.47; p<0.001 for both) and IMT (r=0.31 and 0.36; p<0.01 for both) adjusted by age and sex. Moreover, asymptomatic subjects with plaques have higher PRX-1 and TRX plasma levels (p<0.01 for both). These data were confirmed in a second study in which patients with carotid atherosclerosis showed higher PRX-1 and TRX plasma levels than healthy subjects (p<0.001 for both). In human atherosclerotic plaques, the NADPH oxidase subunit p22phox colocalized with TRX-1/PRX-1 in macrophages (immunohistochemistry). In monocytes and macrophages, phorbol 12-myristate 13-acetate (PMA) induced NADPH activation and TRX-1/PRX-1 release to the extracellular medium, with a concomitant decrease in their intracellular levels, which was reversed by the NADPH inhibitor apocynin (Western blot). In loss-of-function experiments, genetic silencing of the NADPH oxidase subunit Nox2 blocked PMA-induced intracellular TRX-1/PRX-1 downregulation in macrophages. Furthermore, the PMA-induced release of TRX-1/PRX-1 involves the modulation of their redox status and exosome-like vesicles. TRX-1/PRX-1 levels are associated with NADPH oxidase-activity in vivo and in vitro. These data could suggest a coordinated antioxidant response to oxidative stress in atherothrombosis.
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•TRX-1 and PRDX-1 circulating levels are associated with atherosclerosis severity.•Human primary monocytes show a positive correlation between Nox activity and circulating levels of TRX-1 and PRDX-1.•The catalytic isoform Nox2 plays a key role in the oxidative-induced release of TRX-1 and PRDX-1 to the extracellular milieu.•TRX-1 and PRDX-1 are released from the cells through exosomes, among other mechanisms.
Atherothrombosis remains one of the main causes of morbidity and mortality worldwide. The underlying pathology is a chronic pathological vascular remodeling of the arterial wall involving several ...pathways, including oxidative stress. Cellular and animal studies have provided compelling evidence of the direct role of oxidative stress in atherothrombosis, but such a relationship is not clearly established in humans and, to date, clinical trials on the possible beneficial effects of antioxidant therapy have provided equivocal results. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of the main sources of reactive oxygen species (ROS) in human atherothrombosis. Moreover, leukocyte-derived myeloperoxidase (MPO) and red blood cell-derived iron could be involved in the oxidative modification of lipids/lipoproteins (LDL/HDL) in the arterial wall. Interestingly, oxidized lipoproteins, and antioxidants, have been analyzed as potential markers of oxidative stress in the plasma of patients with atherothrombosis. In this review, we will revise sources of ROS, focusing on NADPH oxidase, but also on MPO and iron. We will also discuss the impact of these oxidative systems on LDL and HDL, as well as the value of these modified lipoproteins as circulating markers of oxidative stress in atherothrombosis. We will finish by reviewing some antioxidant systems and compounds as therapeutic strategies to prevent pathological vascular remodeling.
Autoantibodies are the hallmark of autoimmunity, and specifically, antinuclear antibodies (ANA) are one of the most relevant antibodies present in systemic autoimmune diseases (AID). In the present ...study, we evaluate the relationship between ANA and sociodemographic and biobehavioral factors in a population with a low pre-test probability for systemic AID. ANA were determined in serum samples at baseline visit from 2997 participants from the Camargo Cohort using indirect immunofluorescence assay, and two solid phase assays (SPA), addressable laser bead immunoassay, and fluorescence enzyme immunoassay. Sociodemographic and biobehavioral features of the subjects were obtained at baseline visit using a structured questionnaire. The prevalence of ANA positive results was significantly higher when indirect immunofluorescence assay was used as screening method in comparison with SPAs, being higher in females, older subjects, and those with higher C-reactive protein levels. Considering biobehavioral features, the prevalence was higher in those individuals with a sedentary lifestyle, and in ex- and non-alcohol users. Moreover, considering the relevance of the antibody load using ANA Screen, the prevalence of the antibody load also increased with age, especially in females. In conclusion, the prevalence of ANA varies depending on sociodemographic and biobehavioral features of the subjects, which could be relevant specifically in a population with a low pre-test probability for systemic AIDs.
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