Activation of Nrf2/HO-1 Pathway and Human Atherosclerotic Plaque Vulnerability:an In Vitro and In Vivo Study

Susanna Fiorelli, Benedetta Porro, Nicola Cosentino, Alessandro Di Minno, Chiara Maria Manega, Franco Fabbiocchi, Giampaolo Niccoli, Francesco Fracassi, Simone Barbieri, Giancarlo Marenzi, Filippo Crea, Viviana Cavalca, Elena Tremoli, Sonia Eligini

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Issue number4
Publication statusPublished - Apr 16 2019


  • Aged
  • Antioxidants/metabolism
  • Atherosclerosis/metabolism
  • Coronary Artery Disease/metabolism
  • Female
  • GA-Binding Protein Transcription Factor/metabolism
  • Heme Oxygenase-1/genetics
  • Humans
  • Macrophages/metabolism
  • Male
  • Membrane Proteins/genetics
  • Middle Aged
  • NF-E2-Related Factor 2/genetics
  • Oxidative Stress/physiology
  • Plaque, Atherosclerotic/metabolism
  • Reactive Oxygen Species/metabolism
  • Signal Transduction
  • Tomography, Optical Coherence/methods


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