title: An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques.
abstract: Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4(LTB4), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr-/-mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB4ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Departments of Medicine, Pathology &Cell Biology, and Physiology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.|The Department of Molecular and Cellular Physiology, Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, The Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Hellmann
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Departments of Medicine, Pathology &Cell Biology, and Physiology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Proto
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Departments of Medicine, Pathology &Cell Biology, and Physiology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kuriakose
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, The Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, Mainz D-55131, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dorweiler
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Solomon
authors.affiliation: The Department of Pathology, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Jones
authors.affiliation: Department of Anesthesiology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Heyer
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, The Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Spite
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Departments of Medicine, Pathology &Cell Biology, and Physiology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas