Abstract
Neutrophils have been implicated in the pathogenesis of atherosclerosis, a lipid-driven disease of arteries, but they are seldom found in atherosclerotic plaques. To resolve this longstanding paradox, we investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Clinical and pre-clinical studies revealed that levels of circulating neutrophil microvesicles were enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulated at disease-prone regions of arteries that are exposed to complex flow patterns, and they promoted vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, it was demonstrated that neutrophil microvesicles promoted inflammatory gene expression by delivering a microRNA (miR-155) that enhanced NF-κB activation. Similary, neutrophil microvesicles increased miR-155 and enhanced NF-κB at disease-prone sites of disturbed flow in arteries of mice. We conclude that delivery of microvesicles carrying miR-155 to disease-prone regions of arteries provides a novel mechanism by which neutrophils contribute to vascular inflammation and atherogenesis.
Non-standard Abbreviations and Acronyms
- ApoE−/−
- apolipoprotein E deficient
- HCAEC
- human coronary artery endothelial cells (HCAEC)
- ICAM-1
- intercellular adhesion molecule-1
- miRs
- micro RNA
- MVs
- microvesicles
- NETosis
- neutrophil exracellular trap formation
- NF-κB
- nuclear factor
- NMVs
- neutrophil-derived microvesicles
- OSS
- oscillatory shear stress
- qPCR
- quantitative polymerase chain reaction
- RT-PCR
- reverse transcription polymerase chain reaction
- REE
- resting energy expenditure
- TNF
- tumor necrosis factor
- TRPS
- tunable Resistive Pulse Sensing
- VCAM-1
- vascular cell adhesion molecule-1
Non-standard Abbreviations and Acronyms
- ApoE−/−
- apolipoprotein E deficient
- HCAEC
- human coronary artery endothelial cells (HCAEC)
- ICAM-1
- intercellular adhesion molecule-1
- miRs
- micro RNA
- MVs
- microvesicles
- NETosis
- neutrophil exracellular trap formation
- NF-κB
- nuclear factor
- NMVs
- neutrophil-derived microvesicles
- OSS
- oscillatory shear stress
- qPCR
- quantitative polymerase chain reaction
- RT-PCR
- reverse transcription polymerase chain reaction
- REE
- resting energy expenditure
- TNF
- tumor necrosis factor
- TRPS
- tunable Resistive Pulse Sensing
- VCAM-1
- vascular cell adhesion molecule-1