Arsenic, Reactive Oxygen, and Endothelial Dysfunction

Abstract

Human exposure to drinking water contaminated with arsenic is a serious global health concern and predisposes to cardiovascular disease states, such as hypertension, atherosclerosis, and microvascular disease. The most sensitive target of arsenic toxicity in the vasculature is the endothelium, and incubation of these cells with low concentrations of arsenite, a naturally occurring and highly toxic inorganic form of arsenic, rapidly induces reactive oxygen species (ROS) formation via activation of a specific NADPH oxidase (Nox2). Arsenite also induces ROS accumulation in vascular smooth muscle cells, but this is relatively delayed because, depending on the vessel from which they originate, these cells often lack Nox2 and/or its essential regulatory cytosolic subunits. The net effect of such activity is attenuation of endothelium-dependent conduit artery dilation via superoxide anion-mediated scavenging of nitric oxide (NO) and inhibition and downregulation of endothelial NO synthase, events that are temporally matched to the accumulation of oxidants across the vessel wall. By contrast, ROS induced by the more toxic organic trivalent arsenic metabolites (monomethylarsonous and dimethylarsinous acids) may originate from sources other than Nox2. As such, the mechanisms through which vascular oxidative stress develops in vivo under continuous exposure to all three of these potent arsenicals are unknown. This review is a comprehensive analysis of the mechanisms that mediate arsenic effects associated with Nox2 activation, ROS activity, and endothelial dysfunction, and also considers future avenues of research into what is a relatively poorly understood topic with major implications for human health.

ATM directs DNA damage responses and proteostasis via genetically separable pathways

“…S2)(27). Arsenite is thought to induce ROS through activation of NADPH oxidase (Nox) isoforms as well as through the mitochondria (28, 29) and can produce both superoxide as well as hydrogen peroxide in the cytoplasm. Arsenite is stable in serum-containing media over long periods unlike exogenously added hydrogen peroxide (30, 31) and has been reported to induce checkpoint responses mediated by caffeine-sensitive protein kinases (26).…”

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

“…Quercetin ameliorated atherosclerosis via suppressing ROS production in mice after fructose feeding ROS has been well known as an essential factor contributing to tissue injury via inflammation and apoptosis regulation in many diseases [24]. In this regard, we attempted to investigate whether ROS was involved in high fructose feeding-induced atherosclerosis.…”

Endothelium‐Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions

“…In isolated porcine coronary arteries and in patients with CAD, levels of CYP-derived ROS may reach levels that significantly attenuate NO-mediated vasodilation [49]. ECs are also capable of producing ROS from a number of other sources, including several NADPH oxidase (Nox) isoforms, the mitochondrial electron transport chain, uncoupled NOSs, xanthine oxidase, COXs and lipooxygenases ([142, 42]; Figure 2). The majority of these sources reduce molecular O 2 to produce ${{\mathrm{O}}_2}^{{•}_{-}}$, which reacts rapidly with NO to form ONOO − , thus reducing NO bioavailability and associated dilator responses [51].…”