NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis

Anja Hofmann; Frieda Frank; Steffen Wolk; Albert Busch; Anna Klimova; Pamela Sabarstinski; Michael Gerlach; Dmitry Egorov; Irakli Kopaliani; Sönke Weinert; Bianca Hamann; David M Poitz; Coy Brunssen; Henning Morawietz; Katrin Schröder; Christian Reeps

doi:10.1016/j.redox.2022.102473

NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis

Redox Biol. 2022 Nov:57:102473. doi: 10.1016/j.redox.2022.102473. Epub 2022 Sep 26.

Authors

Affiliations

¹ Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Germany. Electronic address: Anja.Hofmann2@uniklinikum-dresden.de.
² Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Germany.
³ Core Unit Data Management and Analytics, National Center for Tumor Diseases Dresden, Partner Site Dresden, University Cancer Center (NCT/UCC), Dresden, Germany.
⁴ Core Facility Cellular Imaging (CFCI), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁵ Institute for Physiology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁶ Internal Medicine, Department of Cardiology and Angiology, Health Campus Immunology, Infectiology and Inflammation, Magdeburg University, Magdeburg, Germany.
⁷ Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁸ Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁹ Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.

Abstract

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis.

Keywords: Atherosclerosis; Carotid artery stenosis; NADPH oxidase 4; Plaques.