Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction.

Background: Cardiac surgery can lead to dysregulation with a proinflammatory state, resulting in adverse outcomes. Hemadsorption using the AN-69 membrane (Oxiris membrane, Baxter, USA) has the properties to chelate inflammatory cytokines. The authors hypothesized that in patients at high risk of inflammation, the use of the Oxiris membrane could decrease inflammation, preserve endothelial function, and improve postoperative outcomes. Methods: The authors conducted a randomized single-center study at Amiens University Hospital (Amiens, France). The study population consisted of adult patients admitted for scheduled cardiac surgery with an expected cardiopulmonary bypass (CPB) time greater than 90 min. The patients were allocated to either the standard group or the Oxiris group. The intervention consisted of using the Oxiris membrane on a Prismaflex device (Baxter, USA) at a blood flow rate of 450 ml/min during CPB. The primary outcome was the assessment of microcirculation on day 1 after surgery by measuring sublingual microcirculation using the microvascular flow index. Microvascular flow index reflects the microcirculation flow type and is graded from 0 to 3 as follows: 0, no flow; 1, intermittent flow; 2, sluggish flow; 3, continuous flow. The secondary outcome was a composite adverse outcome within 30 days after surgery. Cytokines and endothelial biomarkers were measured in all patients at different time points. An intention-to-treat analysis was performed. Results: From October 2019 to November 2022, the study included 70 patients. Two patients were excluded from the Oxiris group: one patient did not undergo surgery, and one procedure was performed under deep hypothermia. The microvascular flow index did not differ between groups on day 1 from baseline: difference (95% CI) Oxiris minus standard at –0.17 (–0.44 to 0.10); P = 0.2. The occurrence of a composite adverse outcome did not significantly differ between groups (14 [42%] for the Oxiris group vs. 12 [35%] for the standard group; P = 0.7). The overall variation in cytokines and angiopoietins did not significantly differ between groups. Conclusions: In patients scheduled for a cardiac surgery with prolonged CPB, the authors could not demonstrate the benefit on microcirculation and major cardiovascular events.

DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of t-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by t-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids.

Vascular calcification (VC), a common pathological condition, is a strong predictor of cardiovascular events and associated mortality. Development and progression of VC heavily rely on vascular smooth muscle cells (VSMCs) and are closely related to oxidative stress, inflammation, and remodelling of extracellular matrix (ECM). Copper (Cu), an essential microelement, participates in these processes, however its involvement in pathophysiology of VC and VSMCs physiology remains poorly investigated. In the present study we analysed Cu impact on the calcification of human aortic primary VSMCs induced in vitro by treatment with high calcium and phosphate levels. Supplementation with physiological micromolar Cu significantly reduced the amount of calcium deposited on VSMCs as compared to moderate deficiency, Cu restriction with chelators or Cu excess. Moreover, optimal concentrations of Cu ions increased protein production by VSMCs, stimulated their metabolic activity, inhibited alkaline phosphatase activity associated with cell-conditioned medium and cellular lysates, and prevented osteogenic differentiation of VSMCs. RNA-seq results indicated that high calcium and phosphate treatments activated many pathways related to oxidative stress and inflammation in VSMCs at the initial stage of calcification. At the same time, expression of VSMC-specific markers and certain components of ECM were downregulated. Supplementation of calcifying cells with 10 μM Cu prevented most of the transcriptomic alterations induced by high calcium and phosphate while chelation-mediated restriction of Cu greatly aggravated them. In summary, physiological concentration of Cu impedes in vitro calcification of VSMCs, prevents their osteogenic transition and minimises early phenotypic alterations induced by high calcium and phosphate, thereby underlining the importance of Cu homeostasis for the physiology of VSMCs, one of the cornerstones of cardiovascular health. Our data suggest that peculiarities of Cu metabolism and its status should be considered when developing preventive and therapeutic approaches for cardiovascular diseases.