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
Affiliations
Susanna Fiorelli
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Benedetta Porro
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Nicola Cosentino
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Alessandro Di Minno
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Chiara Maria Manega
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Franco Fabbiocchi
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Giampaolo Niccoli
Department of Cardiovascular & Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli, I.R.C.C.S., Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Francesco Fracassi
Department of Cardiovascular & Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli, I.R.C.C.S., Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Simone Barbieri
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Giancarlo Marenzi
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Filippo Crea
Department of Cardiovascular & Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli, I.R.C.C.S., Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Viviana Cavalca
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Elena Tremoli
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
Sonia Eligini
Centro Cardiologico Monzino, I.R.C.C.S., 20138 Milan, Italy
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.
