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

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. Key question: How is plaque NOX4 mRNA expression regulated and correlated to plaque stabilizing mechanisms in patients with symptomatic and asymptomatic carotid artery stenosis at a clinically relevant stage of disease?Key finding: Plaque NOX4 mRNA expression is lower in symptomatic carotid artery stenosis and low NOX4 is associated with an increased risk for symptomatic disease. Apoptosis and plaque hemorrhage inversely correlate with plaque NOX4 mRNA expression and healing of a ruptured plaque appears to be improved in plaques with high NOX4 mRNA expression.Take-home Message: Our data support a link between NOX4 mRNA expression and plaque stability in humans with late-stage carotid artery stenosis. [Display omitted] •Plaque NOX4 mRNA expression is lowered in symptomatic carotid artery disease.•A low plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome.•High NOX4 mRNA expression was linked to plaque stabilizing mechanisms.•An increased NOX4 mRNA expression could suppo