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Review
. 2023 May;38(13-15):1022-1040.
doi: 10.1089/ars.2022.0204. Epub 2023 Mar 7.

The Role of Oxidants in Percutaneous Coronary Intervention-Induced Endothelial Dysfunction: Can We Harness Redox Signaling to Improve Clinical Outcomes?

Kathryn Wolhuter  1   2 , Stephanie M Y Kong  1 , Christopher P Stanley  3 , Jason C Kovacic  1   4   5
Affiliations
Review

The Role of Oxidants in Percutaneous Coronary Intervention-Induced Endothelial Dysfunction: Can We Harness Redox Signaling to Improve Clinical Outcomes?

Kathryn Wolhuter et al. Antioxid Redox Signal. 2023 May.

Abstract

Significance: Coronary artery disease (CAD) is commonly treated using percutaneous coronary interventions (PCI). However, PCI with stent placement damages the endothelium, and failure to restore endothelial function may result in PCI failure with poor patient outcomes. Recent Advances: Oxidative signaling is central to maintaining endothelial function. Potentiation of oxidant production, as observed post-PCI, results in endothelial dysfunction (ED). This review delves into our current understanding of the physiological role that endothelial-derived oxidants play within the vasculature and the effects of altered redox signaling during dysfunction. We then examine the impact of PCI and intracoronary stent placement on oxidant production in the endothelium, which can culminate in stent failure. Finally, we explore how recent advances in PCI and stent technologies aim to mitigate PCI-induced oxidative damage and improve clinical outcomes. Critical Issues: Current PCI technologies exacerbate cellular oxidant levels, driving ED. If left uncontrolled, oxidative signaling leads to increased intravascular inflammation, restenosis, and neoatherosclerosis. Future Directions: Through the development of novel biomaterials and therapeutics, we can limit PCI-induced oxidant production, allowing for the restoration of a healthy endothelium and preventing CAD recurrence.

Keywords: CAD; PCI; endothelial dysfunction; oxidants; redox signaling.

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Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
The impact of PCI on vessels. In a healthy artery, the endothelium (a single layer of ECs) acts as the barrier between the artery wall and the bloodstream. The endothelium also regulates the proliferation, constriction, and relaxation of VSMCs in the media. In CAD, arteries become stenotic from the development of atherosclerotic plaque, the endothelium becomes dysfunctional, and VSMCs become dysregulated. In the early stages after PCI with stent placement, the lumen area is restored but vascular injury causes endothelial denudation, ED, and increased inflammation. This leads to increased recruitment and infiltration of inflammatory cells into the media. In later stages, neointimal hyperplasia develops from the proliferation and migration of VSMCs into the intima. Neoatherosclerosis then develops within the neointima because of increased inflammatory cell infiltration. In-stent thrombosis can also occur due to delayed re-endothelialization. CAD, coronary artery disease; EC, endothelial cell; ED, endothelial dysfunction; PCI, percutaneous coronary interventions; VSMC, vascular smooth muscle cell.
FIG. 2.
FIG. 2.
Endothelial sources of •NO, RNS, and ROS. (A) Endothelial sources of •NO and RNS. l-Arginine is converted to •NO by eNOS ①. To form RNS, •NO reacts with O2•− to form OONO− and peroxynitrous acid (not shown) or is degraded to form •NO2 and NO−3 ②. •NO also reacts with proteins containing Fe2+-heme, forming NO+, N2O4, or N2O3 ③. (B) Endothelial sources of ROS. O2•− production is via activation of enzymes such as uncoupled eNOS, CYP450, and XO, as well as increased mitochondrial respiration or increased NOX activity. Once formed, O2•− is dismutated by SOD to form H2O2. Alternatively, H2O2 is formed directly by various NOX isoforms ④. O2•− and H2O2 react with transition metals (through Fenton reactions) or HOCl to form •OH ⑤. •OH can be formed as a minor product of OONO− degradations ⑥. eNOS, endothelial nitric oxide synthase; H2O2, hydrogen peroxide; HOCl, hypochlorous acid; •NO, nitric oxide; •NO2, nitrogen dioxide; NO−3, nitrate; •OH, hydroxyl radicals; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; XO, xanthine oxidase.
FIG. 3.
FIG. 3.
•NO, RNS, and ROS in endothelial function and dysfunction. In functional ECs, stimulus-induced eNOS activity elevates •NO production. •NO mediates relaxation of VSMCs via binding to the Fe2+-heme of sGC, which increases cGMP and canonically activates PKG1α. •NO signaling also regulates vascular tone by opening VSMC ion channels (yellow open channel) directly, or via RNS-mediated oxidation of SERCA. H2O2 stabilizes eNOS and regulates arterial tone and blood pressure through cGMP-independent activation of PKG1α. In addition, •NO signaling inhibits platelet aggregation through cGMP signaling, RNS-mediated SNO of platelet proteins, and inhibition of EC adhesion proteins (yellow and purple EC projections). In EC dysfunction, oxidation of the eNOS cofactor BH4 to BH2 uncouples eNOS leading to increased production of O2•− and H2O2. Elevated expression of NOX and oxidant leak from the mitochondria further contribute to O2•−, H2O2, and OONO− levels. Dysregulated oxidant production leads to irreversible oxidations of SERCA, sGC heme, and TRPV4 rendering them inactive and unable to regulate vascular tone. The dominant mechanism of arterial relaxation under these conditions is through oxidative activation of PKG1α, however, prolonged exposure to H2O2 results in EC and VSMC apoptosis. Loss of •NO bioavailability enhances platelet aggregation, adhesion factor expression, and VSMC proliferation. BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; cGMP, 3′,5′-cyclic guanosine monophosphate; PKG1α, protein kinase G subunit 1α; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; sGC, soluble guanylate cyclase; SNO, S-nitrosation.
FIG. 4.
FIG. 4.
ED is induced by flow disruption. ① Stent implantation typically creates turbulent flow that increases NOX expression in ECs. NOX-derived O2•− increases thrombus risk by elevating the expression of vWF and increasing intracellular ROS production within ECs through activation of XO and ② uncoupling of eNOS via the oxidation of BH4 to BH2, which also decreases NO bioavailability. ③ Downstream signaling from NOX regulatory subunit p47phox leads to elevated expression of EC adhesion factors including P-selectin, ICAM, and VCAM. ④ This increases the recruitment of inflammatory neutrophils to the subendothelial space. MPO within activated neutrophils produces HOCl, which leads to damaging lipid peroxidation, and reduces NO bioavailability through the metabolism of •NO to NO2−. ICAM, intercellular adhesion molecule; MPO, myeloperoxidase; VCAM, vascular cell adhesion molecule; vWF, von Willebrand factor.
FIG. 5.
FIG. 5.
Therapeutics targeting Hmox1 to reduce oxidative damage. Antioxidants probucol, resveratrol, and quercetin have been trialed as alternative compounds in association with DES. The uptake of these antioxidants by ECs and VSMCs activates the Nrf2 signaling pathway, through which cytosolic Nrf2 translocates to the nucleus and binds to antioxidant response elements in promoter regions of specific antioxidant response enzymes. The Nrf2 signaling pathway induces expression of Hmox1, which catalyzes the degradation of heme to biliverdin, releasing Fe2+ and CO as by-products, and then, biliverdin is quickly reduced to bilirubin by BVRA. Hmox1 promotes re-endothelialization by decreasing cytosolic heme, which reduces ROS, releasing CO that protects EC from apoptosis, and by increasing antioxidant bilirubin levels, which increase •NO and promote EC function. Increased •NO in EC also facilities inhibition of VSMC proliferation. Induction of Hmox1 expression via Nrf2 signaling, as well as Hmox1-associated CO, can activate the YY1 transcription factor, which in turn activates the cell proliferation response and feeds back to further promote Hmox1 expression. In VSMC, YY1 inhibits VSMC proliferation, which reduces neointimal hyperplasia and restenosis. BVRA, biliverdin reductase; DES, drug-eluting stents; Hmox1, heme oxygenase-1; Nrf2, nuclear factor E2-related factor 2; YY1, Yin Yang 1.
FIG. 6.
FIG. 6.
NOX-derived superoxide plays a central role in neoatherosclerosis. As the endothelium repairs, prolonged exposure to stent struts results in the activation of NOX, which drives the formation of neoatherosclerosis. NOX-signaling decreases SOD expression leading to the accumulation of ROS within EC. NOX-derived ROS also increase Sp1-mediated transcription of Cav-1. Cav-1 expression inhibits the Nrf2-mediated antioxidant response and TrxR, resulting in a diminished capacity for ECs to remove oxidants. NOX signaling activates the kinase c-Abl promoting Cav-1 and dynamin-2 phosphorylation, which together elevate the formation and endocytosis of lipid-laden caveolae. High ROS drive the oxidation of intracellular and extracellular lipids within the arterial wall, accelerating the formation of neoatherosclerotic plaques. Cav-1, caveolin-1; TrxR, thioredoxin reductase.
FIG. 7.
FIG. 7.
NO-elevating biomaterials. Novel biomaterials including PCU-SS (A), NO hydrogel (B), and Zn2+ bound to catechol-grafted chitosan (C) contain domains (in purple) designed to increase NO bioavailability through the reduction of circulating S-nitrosothiol, predominantly GSNO. (D) Mechanistically, PCU-SS and the NO hydrogel reduce the labile S-nitrosobond in GSNO via nucleophilic attack, resulting in S-glutathiolation of stent surface thiol (or selenium, not shown) and the release of a reactive nitrogen species (NOX). The biomaterial is regenerated using GSH. (E) Elevation of NOX may be detrimental to EC function due to the ability to oxidize BH4 to BH2, resulting in eNOS uncoupling and a decrease in •NO production, and inhibitory S-glutathiolation of SERCA. However, elevated NOX may compensate for decreased •NO by promoting oxidant-mediated vasodilation via disulfide PKG1α in VSMCs. GSH, reduced glutathione; GSNO, S-nitrosoglutathione; PCU-SS, sulfur-mediated polycarbonate polyurethane.
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