Abstract
Reactive oxygen species (ROS) induce nuclear factor erythroid 2–related factor 2 (Nrf2) activation as an adaptive defense mechanism, determining the synthesis of antioxidant molecules, including heme-oxygenase-1 (HO-1). HO-1 protects cells against oxidative injury, degrading free heme and inhibiting ROS production. HO-1 is highly expressed in macrophages during plaque growth. Macrophages are morpho-functionally heterogeneous, and the prevalence of a specific phenotype may influence the plaque fate. This heterogeneity has also been observed in monocyte-derived macrophages (MDMs), a model of macrophages infiltrating tissue. The study aims to assess oxidative stress status and Nrf2/HO-1 axis in MDM morphotypes obtained from healthy subjects and coronary artery disease (CAD) patients, in relation to coronary plaque features evaluated in vivo by optical coherence tomography (OCT). We found that MDMs of healthy subjects exhibited a lower oxidative stress status, lower Nrf2 and HO-1 levels as compared to CAD patients. High HO-1 levels in MDMs were associated with the presence of a higher macrophage content, a thinner fibrous cap, and a ruptured plaque with thrombus formation, detected by OCT analysis. These findings suggest the presence of a relationship between in vivo plaque characteristics and in vitro MDM profile, and may help to identify patients with rupture-prone coronary plaque.
Highlights
The progression of coronary atherosclerotic plaque and its destabilization with plaque rupture and thrombus formation are the key mechanisms of acute myocardial infarction (AMI) [1,2]
In our more recent study, we demonstrated that the peculiar morpho-phenotype profile of monocyte-derived macrophages (MDMs) isolated from coronary artery disease (CAD) patients is associated with the characteristics of coronary vulnerable plaque, as assessed by optical coherence tomography (OCT) [29]
We investigated HO-1 levels and the activation of nuclear factor erythroid 2–related factor 2 (Nrf2)/HO-1 axis in different MDM morphotypes obtained from healthy subjects and CAD patients, in relation to coronary plaque morphology and activity, as analyzed in vivo by OCT
Summary
The progression of coronary atherosclerotic plaque and its destabilization with plaque rupture and thrombus formation are the key mechanisms of acute myocardial infarction (AMI) [1,2]. Macrophages are versatile cells and, in relation to microenvironmental stimuli, they respond by activating different signal. At coronary atherosclerotic plaque level, macrophage population is characterized by morphological and functional heterogeneity that may enhance plaque growth and/or rupture [4]. An increasing body of evidence suggests that oxidative stress is closely associated with the atherosclerotic process and plaque instability [5,6] through different pathological mechanisms, including endothelial dysfunction, lipid oxidation, expression of adhesion molecules, and monocyte recruitment [7,8,9]. In response to oxidative stress stimuli, cells implement several defense mechanisms and, among them, the activation of nuclear erythroid factor 2 – related factor 2 (Nrf2)/heme oxygenase-1
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