Limiting reductive stress for treating in-stent stenosis: the heart of the matter?

Vascular injury and drivers of stenosis Balloon angioplasty and stenting (BAS) remains the preferred method of treatment for flow-limiting atherosclerosis, far outnumbering coronary artery bypass grafting (1). Unfortunately, stent-mediated intimal hyperplasia, a consequence of vascular smooth muscle cell (VSMC) proliferation, remains a cause of restenosis after BAS and often presents with acute coronary syndrome. Reendothelialization of the damaged vessel has been proposed to reduce intimal hyperplasia; however, current treatment options, such as drugeluting stents, aimed at limiting VSMC proliferation may also inhibit reendothelialization. Reduced reendothelialization leads to an increased risk of thrombosis within the stented vessel, often resulting in devastating clinical consequences (2). Thus, there is a clinical need for improvements in the treatment of flow-limiting atherosclerosis. Recent advances have been made in preclinical models, including the use of mesenchymal stem cells (3) and miRNA-based strategies (4), to assist with reendothelialization. The potential for these new approaches to lead to clinical breakthroughs will likely be expedited once the mechanisms behind BAS-driven hyperplasia are better understood. Over the past decade, there has been a groundswell of clinical and preclinical evidence that indicates the antioxidant enzyme glutathione peroxidase-1 (GPX1) is involved in the atherogenic process. Clinically, low levels of GPX1 have been associated with an increased risk of cardiovascular events in patients with coronary artery disease, independent of traditional risk factors (5), and GPX1 activity has also been shown to be reduced in excised human plaques (6). Preclinically, plaque analysis in atherosclerosis-prone mice revealed that a lack of GPX1 accelerates plaque formation under both hyperlipidemic (7) and diabetic (8) conditions. While previous studies on GPX1 in vascular injury have focused on its role in atherosclerosis, particularly the involvement of GPX1 in immune cells (9), the role of GPX1 in VSMCs, the drivers of stenosis, has not been characterized. In this issue of the JCI, Ali et al. (10) demonstrate that vascular injury–induced loss of GPX1 alters oxidoreductive stress in VSMCs and promotes in-stent stenosis. This study opens up new frontiers for in-stent stenosis research and therapy and also highlights the need to look further afield at reductive stress when dealing with imbalances in redox events. GPX1 is known to perform important functions in limiting reactive oxygen species–mediated lipid, protein, and DNA damage (11); therefore, the oxidative stress that results from a decline in GPX1 levels has been touted as the mediator of injury. The current report from Ali and colleagues necessitates reevaluation of this paradigm and identifies additional biochemical mechanisms that involve reductive stress and are modulated as a result of GPX1dependent pathways.