Nanoparticles in Medicine: A Focus on Vascular Oxidative Stress

Abstract

Nanotechnology has had a significant impact on medicine in recent years, its application being referred to as nanomedicine. Nanoparticles have certain properties with biomedical applications; however, in some situations, they have demonstrated cell toxicity, which has caused concern surrounding their clinical use. In this review, we focus on two aspects: first, we summarize the types of nanoparticles according to their chemical composition and the general characteristics of their use in medicine, and second, we review the applications of nanoparticles in vascular alteration, especially in endothelial dysfunction related to oxidative stress. This condition can lead to a reduction in nitric oxide (NO) bioavailability, consequently affecting vascular tone regulation and endothelial dysfunction, which is the first phase in the development of cardiovascular diseases. Therefore, nanoparticles with antioxidant properties may improve vascular dysfunction associated with hypertension, diabetes mellitus, or atherosclerosis.

Figure 1

Generalized diagram of the types of nanoparticles and their main biomedical applications. Based on their chemical composition, nanoparticles can be divided into three main groups: organic, inorganic, and carbon-based. Each category includes several types of nanoformulations.

Figure 2

The Nox 4 paradox. Vascular Nox 4 generates superoxide anion (O₂⁻) and hydrogen peroxide (H₂O₂). Depending on which via predominates, Nox 4 activation can be damaging or protective. VSCMs: vascular smooth muscle cells.

Figure 3

Endothelial dysfunction due to oxidative stress. The image shows how vascular oxidative stress leads to endothelial dysfunction. (a) represents the production of nitric oxide (NO) from L-arginine by endothelial nitric oxide synthase (eNOS) in a healthy endothelium, where levels of superoxide anion (O₂⁻) are low. NO diffuses from the endothelium to the vascular smooth muscle, where it activates soluble guanylate cyclase (sGC), which increases the levels of guanosine 3′,5′ cyclic monophosphate (cGMP), thus leading to vasodilation. (b) represents acute vascular oxidative stress, with an increase in O₂⁻ production, followed by an increase in peroxynitrite (ONOO⁻) levels. ONOO⁻ produces endothelial dysfunction by directly reducing the NO available for activating sGC and by reducing prostaglandin I₂ (PGI₂) content via nitration PGI₂ synthase. If oxidative stress is persistent (c), eNOS becomes uncoupled, producing O₂⁻ instead of NO and aggravating endothelial dysfunction.

Figure 4

Chronic activation of the renin-angiotensin system (RAS) contributes to oxidative stress and vascular dysfunction. Increased levels of angiotensin II (AT II) lead to endothelial dysfunction through AT II receptor 1 (AT1R) activation, which in turn induces vascular oxidative stress by increasing NADPH oxidase (Nox) activity and xanthine oxidase (XO) expression. Both enzymes produce superoxide anion (O₂⁻), which scavenges nitric oxide (NO) by forming peroxynitrite (ONOO⁻), consequently decreasing NO bioavailability and causing endothelial dysfunction. Moreover, AT II can undermine the induction of the antioxidant system thioredoxin (TRX), enhancing levels of H₂O₂ and contributing to vascular oxidative stress. H₂O₂ is the most stable and abundant ROS which, as a signalling messenger, maintains physiologic vascular homeostasis, but its overproduction is related to vascular dysfunction. In contrast, AT II receptor 2 (AT2R) activation can counteract the lesser NO bioavailability induced by vascular oxidative stress via eNOS phosphorylation, thereby increasing its activity.

Figure 5

Effects of nanoparticles on the main mechanisms of vascular oxidative stress and antioxidant systems. Mitochondrial respiratory chain enzymes, xanthine oxidase (XO), NADPH oxidase (Nox), and uncoupled endothelial NO synthase (eNOS) are the main sources of superoxide anion (O₂⁻) in the vascular wall. O₂⁻ can produce hydroxil radical (OH), hydrogen peroxide (H₂O₂), and peroxynitrite (ONOO⁻). The enzymes that decompose H₂O₂ are catalase, glutathione, thioredoxin peroxidase, and peroxiredoxin. In inflammation, the induction of iNOS produces high levels of NO which react with mitochondrial respiratory chain enzymes and increase O₂⁻ production. Some nanoparticles (NPs), such as nanoceria, have demonstrated the ability to reduce the expression of iNOS. Moreover, nanoceria can scavenge both NO and OH, thus proving to be anti-inflammatory and antioxidant agents. Some NPs increase Nox activity and can be used as antitumoral agents. The role of Nox 4 in vascular function is controversial; whereas some studies report a protective role against atherogenesis, others show the contrary. Certain NPs can be used as NO donors to reverse endothelial dysfunction. Some NPs exert SOD, catalase, oxidase, phosphatase, and peroxidase-mimetic activities.