1. Expansion of necrotic core and shedding of Mertk receptor in human carotid plaques: a role for oxidized polyunsaturated fatty acids?
- Author
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Chiara Mozzini, Gian Cesare Guidi, Luciano Cominacini, Stefania Manfro, Anna Fratta Pasini, Chiara Stranieri, Ulisse Garbin, Giovanni Lipari, Andrea Pasini, Flavia Merigo, Paola Vallerio, and Elda Baggio
- Subjects
Carotid Artery Diseases ,Male ,Conjugated ,Physiology ,genetics/metabolism ,Apoptosis ,ADAM Proteins ,genetics/metabolism, Aged, Apoptosis, Carotid Arteries ,enzymology/pathology, Carotid Artery Diseases ,enzymology/pathology, Cell Line, F2-Isoprostanes ,metabolism, Fatty Acids ,Unsaturated ,metabolism, Female, Humans, Hydroxyeicosatetraenoic Acids ,metabolism, Immunohistochemistry, Intercellular Signaling Peptides and Proteins ,metabolism, Linoleic Acids ,metabolism, Macrophages ,enzymology/pathology, Male, Necrosis, Oxidation-Reduction, Phagocytosis, Plaque ,Atherosclerotic, Proto-Oncogene Proteins ,metabolism, RNA Interference, Receptor Protein-Tyrosine Kinases ,metabolism, Transfection ,Apoptotic cell clearance ,Hydroxyeicosatetraenoic Acids ,Linoleic Acids, Conjugated ,enzymology/pathology ,Plaque ,Atherosclerotic ,F2-Isoprostanes ,Fatty Acids ,Immunohistochemistry ,Plaque, Atherosclerotic ,Carotid Arteries ,Linoleic Acids ,Biochemistry ,Fatty Acids, Unsaturated ,Intercellular Signaling Peptides and Proteins ,Female ,RNA Interference ,Cardiology and Cardiovascular Medicine ,Oxidation-Reduction ,Tyrosine kinase ,Phagocytosis ,ADAM17 Protein ,Biology ,C-Mer Tyrosine Kinase ,Transfection ,Cell Line ,Necrosis ,Proto-Oncogene Proteins ,Physiology (medical) ,Extracellular ,Humans ,Efferocytosis ,Aged ,c-Mer Tyrosine Kinase ,Macrophages ,Receptor Protein-Tyrosine Kinases ,MERTK ,Molecular biology ,metabolism - Abstract
Aims Expansion of necrotic core (NC), a major feature responsible for plaque disruption, is likely the consequence of accelerated macrophage apoptosis coupled with defective phagocytic clearance (efferocytosis). The cleavage of the extracellular domain of Mer tyrosine kinase (Mertk) by metallopeptidase domain17 (Adam17) has been shown to produce a soluble Mertk protein (sMer), which can inhibit efferocytosis. Herein, we analysed the expression and localization of Mertk and Adam17 in the tissue around the necrotic core (TANC) and in the periphery (P) of human carotid plaques. Then we studied the mechanisms of NC expansion by evaluating which components of TANC induce Adam17 and the related cleavage of the extracellular domain of Mertk. Methods and results We studied 97 human carotid plaques. The expression of Mertk and Adam17 was found to be higher in TANC than in P ( P < 0.001). By immunohistochemistry, Mertk was higher than Adam17 in the area of TANC near to the lumen ( P < 0.01) but much lower in the area close to NC ( P < 0.01). The extract of this portion of TANC increased the expression (mRNA) of Adam17 and Mertk ( P < 0.01) in macrophage-like THP-1 cells but it also induced the cleavage of the extracellular domain of Mertk, generating sMer in the medium ( P < 0.01). This effect of TANC extract was most evoked by its content in F2-isoprostanes, hydroxyoctadecadienoic acids, and hydroxytetraenoic acids. Conclusion Some oxidized derivatives of polyunsaturated fatty acids contained in TANC of human carotid plaques are strong inducers of Adam17, which in turn leads to the generation of sMer, which can inhibit efferocytosis.
- Published
- 2012
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