Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

Abstract

Atherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology is characterized by chronic inflammation, oxidative stress, gradual accumulation of low-density lipoproteins (LDL) particles and fibrous elements in focal areas of large and medium arteries. These fibrofatty lesions in the artery wall become progressively unstable and thrombogenic leading to heart attack, stroke or other severe heart ischemic syndromes. Elevated blood levels of LDL are major triggering events for atherosclerosis. A cascade of molecular and cellular events results in the atherosclerotic plaque formation, evolution, and rupture. Moreover, the senescence of multiple cell types present in the vasculature were reported to contribute to atherosclerotic plaque progression and destabilization. Classical therapeutic interventions consist of lipid-lowering drugs, anti-inflammatory and life style dispositions. Moreover, targeting oxidative stress by developing innovative antioxidant agents or boosting antioxidant systems is also a well-established strategy. Accumulation of senescent cells (SC) is also another important feature of atherosclerosis and was detected in various models. Hence, targeting SCs appears as an emerging therapeutic option, since senolytic agents favorably disturb atherosclerotic plaques. In this review, we propose a survey of the impact of inflammation, oxidative stress, and senescence in atherosclerosis; and the emerging therapeutic options, including thioredoxin-based approaches such as anti-oxidant, anti-inflammatory, and anti-atherogenic strategy with promising potential of senomodulation.

Keywords: anti-inflammatory agents; antioxidants; atherosclerosis; inflammation; oxidative stress; senescence; senomodulators; thioredoxin.

Figure 1

Role of senescence mediated-processes on the physiopathological events of atherosclerosis. Focus on vascular wall senescent cell populations; namely endothelial cells (EC), macrophages (Mφ), and smooth muscle cells (SMC).

Figure 2

The Redox-Cycling Reactions of the Thioredoxin System. The dithiol moieties of Trx-1 (S-S form) are reduced by receiving electrons from NADPH in the presence of thioredoxin reductase (TrxR). Reduced Trx-1 (SH form) in turn reduces oxidized proteins with disulfide bonds through thiol disulfide exchange reactions. Furthermore, Trx-1 can scavenge free radicals indirectly through peroxiredoxin [157]. Flavin Adenine Dinucleotide (FAD); Nicotinamide Adenine Dinucleotide Phosphate (NADPH₂).

Figure 3

Atherosclerosis triad: targeting inflammatory pathways, oxidative stress, and senescence to derive innovative therapeutic strategies. In atherosclerosis, inflammation, oxidative stress and senescence are interconnected processes (arrows). In this context, main deregulated factors are given for each process together with the principal classes of therapeutic options (green dashed frames), including anti-inflammatory agents (cytokine blockers, inflammasome inhibitors, NF-κB modulators); antioxidants (ROS scavengers, antioxidant system boosters); senolytics; and senormorphics.

Figure 4

Summary of the principal features of thioredoxin system in atherosclerosis. Truncated thioredoxin (Trx-80) acts as an inflammatory and atherosclerosis inducer while Trx-1 and TxMPs counteract key inflammatory pathways and exert an antiatherogenic effect.