An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

Gabrielle Fredman, Jason Hellmann, Jonathan D. Proto, George Kuriakose, Romain A. Colas, Bernhard Dorweiler, E. Sander Connolly, Robert Solomon, David M. Jones, Eric J. Heyer, Matthew Spite () and Ira Tabas ()
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Gabrielle Fredman: Perioperative and Pain Medicine, Pathology & Cell Biology, and Physiology, Columbia University Medical Center
Jason Hellmann: Perioperative and Pain Medicine, The Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School
Jonathan D. Proto: Perioperative and Pain Medicine, Pathology & Cell Biology, and Physiology, Columbia University Medical Center
George Kuriakose: Perioperative and Pain Medicine, Pathology & Cell Biology, and Physiology, Columbia University Medical Center
Romain A. Colas: Perioperative and Pain Medicine, The Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School
Bernhard Dorweiler: University Medical Center of the Johannes Gutenberg University
E. Sander Connolly: Columbia University Medical Center
Robert Solomon: Columbia University Medical Center
David M. Jones: Albany Medical College
Eric J. Heyer: Columbia University Medical Center
Matthew Spite: Perioperative and Pain Medicine, The Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School
Ira Tabas: Perioperative and Pain Medicine, Pathology & Cell Biology, and Physiology, Columbia University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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:LTB4 ratio 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.

Date: 2016
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DOI: 10.1038/ncomms12859

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