Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects

Abstract

Reactive oxygen and nitrogen species (ROS and RNS, e.g. H₂O₂, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. At higher concentrations, ROS and RNS lead to oxidative stress and oxidative damage of biomolecules (e.g. via formation of peroxynitrite, fenton chemistry). Peripheral artery disease (PAD) is characterized by severe ischemic conditions in the periphery leading to intermittent claudication and critical limb ischemia (end stage). It is well known that redox biology and oxidative stress play an important role in this setting. We here discuss the major pathways of oxidative stress and redox signaling underlying the disease progression with special emphasis on the contribution of inflammatory processes. We also highlight therapeutic strategies comprising pharmacological (e.g. statins, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibition) and non-pharmacological (e.g. exercise) interventions. Both of these strategies induce potent indirect antioxidant and anti-inflammatory mechanisms that may contribute to an improvement of PAD associated complications and disease progression by removing excess formation of ROS and RNS (e.g. by ameliorating primary complications such as hyperlipidemia and hypertension) as well as the normalization of the inflammatory phenotype suppressing the progression of atherosclerosis.

Keywords: Antioxidant therapy; Claudication and critical limb ischemia; Oxidative stress; Peripheral artery (occlusive) disease; Redox signaling; Walking distance.

Fig. 1

The three phases of ischemia reperfusion (I/R) damage and recovery that can be also applied to disease mechanisms of peripheral artery disease. The major redox-regulated pathways or ROS sources are illustrated in the scheme. Major players are HIF-1α, NOX1/4, mitochondria, eNOS, XO, Grx-1 either promoting or preventing necrosis/apoptosis, oxidative stress, inflammation and remodeling/angiogenesis. For detailed explanation see main text. Modified from . Abbreviations: HIF-1α, hypoxia-inducible factor 1α; NOX1/4, NADPH oxidase isoform 1 or 4; XOR, xanthine oxidoreductase; deoxy-Hb, deoxy-hemoglobin; eNOS, endothelial nitric oxide synthase; XDH, xanthine dehydrogenase; XO, xanthine oxidase; mPTP, mitochondrial permeability transition pore; MMPs, matrix-metalloproteinases; EPC, endothelial progenitor cells; Grx-1, glutaredoxin-1; VEGF, vascular endothelial growth factor.

Fig. 2

Pathophysiological disabilities associated with peripheral artery disease. Modified from , .

Fig. 3

Correlation of the marker of inflammation soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) with oxidative stress and walking distance in PAD patients with intermittent claudication. We found an inverse correlation for sTREM-1 with the absolute (r=−0.479; p=0.002) (A), a direct correlation with whole blood oxidative burst after phorbol ester stimulation (r=0.565; p=0.0001) (B) and the general markers of inflammation fibrinogen (r=0.532; p=0.0004) (C) and CRP (r =0.263; p=0.1002) (D). Number of patients was n=40. Adapted from . With permission of Springer-Verlag Berlin Heidelberg. Copyright © 2015.

Fig. 4

Positive effects of exercise training on peripheral perfusion in patients with intermittent claudication. (A) Summary of potential beneficial effects of exercise training on PAD. Modified from , , . With permission of Massachusetts Medical Society. Copyright © 2002. (B, C) Original data on decreased oxidative burst in phorbol ester stimulated whole blood (measured by L-012 ECL) and expression of the pro-inflammatory molecule sTREM-1 on monocytes of PAD patients with intermittent claudication after exercise. Number of patients was n=40.Adapted from . With permission of Springer-Verlag Berlin Heidelberg. Copyright © 2015.

Fig. 5

Proposed hypothesis on the role of oxidative stress, neutrophils (PMN) and monocytes in peripheral artery disease (PAD). In PAD patients platelets are strongly activated. Also markers of inflammation like triggering receptor expressed on myeloid cells-1 (TREM-1) were largely increased in plasma of PAD patients. PMN and monocytes are stimulated via Interaction of TREM-ligand with TREM-1, which leads to an increased production of ROS. This will further increase endothelial ROS formation, possibly via NADPH oxidases, which then might activate even more platelets, thus leading to a positive feedback mechanism. The increased burden of vascular ROS will potentially also inhibit endothelial nitric oxide (^•NO) formation, which will ultimately lead to vascular dysfunction and progression of atherosclerosis. Whether mitochondrial ROS are involved in immune cell activation and subsequent tissue damage by infiltrating immune cells is likely but remains to be demonstrated in patients with PAD. sTREM being shedded by PMN and monocytes might further stimulate chronic inflammation or act as a regulatory molecule to regulate the response of the innate immune system to the inflammatory stimulus in atherosclerosis. The scheme summarizes our previous findings , .

Fig. 6

Proposed treatment regimen for patients with PAD. Modified from .