Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

Abstract

Background Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. Main text Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. Conclusions Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.

Immune, Blood Cell, and Blood Gas Biomarkers of Delirium in Elderly Individuals with Hip Fracture Surgery

“…In rat models, increasing oxygen concentrations increase oxidative stress toxicity to red blood cells [45]. These effects could further aggravate the oxidative stress associated with delirium [40, 46] and with inflammatory conditions [47].…”

Ferulic Acid Derivatives and Avenanthramides Modulate Endothelial Function through Maintenance of Nitric Oxide Balance in HUVEC Cells

“…We evaluated one of the possible pathways involved in the regulation of the NO balance, but it cannot be excluded that other intracellular signals are modulated by the tested compounds at the same time. Likewise, further studies will be needed to define the role of these compounds in the eNOS downstream signaling pathways, which may influence the endothelial cells homeostasis by increasing the mitochondrial biogenesis and through the activation of mTOR and the expression of SIRT1 [57][58][59][60]. Overall, our mechanistic investigation explores some vascular mechanisms that complement in vivo investigations [61], providing additional evidence that phenolic acids derived from oats and their metabolites could contribute to the cardiovascular benefits derived from oat consumption.…”

Biomarkers and Clinical Features of Delirium in Elderly Individuals With Hip Fracture Surgery.

“…In rat models, increasing oxygen concentrations increase oxidative stress toxicity to red blood cells (54) . These effects could further aggravate the oxidative stress associated with delirium (49,55) and with inflammatory conditions (56) ..…”