Abstract
ObjectivesPolymorphonuclear neutrophils (PMN) in atherosclerotic plaques have been identified only recently, and their contribution to plaque development is not yet fully understood. In this study, production of elastase, interleukin (IL)-8 and vascular endothelial growth factor (VEGF) by PMN was investigated in subjects with carotid stenosis undergoing carotid endarterectomy (CEA).MethodsThe study enrolled 50 patients (Pts) and 10 healthy subjects (HS). Circulating PMN (cPMN) isolated from venous blood (in both Pts and HS) and from plaques (pPMN, in Pts) were cultured, alone or with 0.1 μM fMLP. Elastase, IL-8 and VEGF mRNA were analyzed by real-time PCR. In CEA specimens, PMN were localized by immunohistochemistry.ResultsIn both Pts cPMN and pPMN, IL-8 mRNA was higher at rest but lower after fMLP (P<0.01 vs HS), and VEGF mRNA was higher both at rest and after fMLP (P<0.01 vs HS), while elastase mRNA was not significantly different. On the contrary, protein production was always higher in cPMN of HS with respect to values measured in cells of Pts. In CEA specimens, CD66b+ cells localized to areas with massive plaque formation close to neovessels. Pts with soft and mix plaques, as defined by computed tomography, did not differ in cPMN or pPMN IL-8, VEGF or elastase mRNA, or in intraplaque CD66b+ cell density. However, Pts with soft plaques had higher white blood cell count due to increased PMN.ConclusionsIn Pts with carotid plaques, both circulating and intraplaque PMN produce IL-8, VEGF and elastase, which are crucial for plaque development and progression. These findings suggest mechanistic explanations to the reported correlation between PMN count and cardiovascular mortality in carotid ATH.
Highlights
Atherosclerosis (ATH) is associated with the accumulation of cholesterol deposits in subendothelial macrophage-derived foam cells and by subsequent adherence and entry of leukocytes into the arterial wall, migration of smooth muscle cells into the intima, activation and aggregation of platelets, endothelial dysfunction, and the production of inflammatory cytokines [1,2,3]
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In both Pts Circulating PMN (cPMN) and possible differences between intraplaque PMN (pPMN), IL-8 mRNA was higher at rest but lower after fMLP (P
Protein production was always higher in cPMN of HS with respect to values measured in cells of Pts
Summary
Atherosclerosis (ATH) is associated with the accumulation of cholesterol deposits in subendothelial macrophage-derived foam cells and by subsequent adherence and entry of leukocytes into the arterial wall, migration of smooth muscle cells into the intima, activation and aggregation of platelets, endothelial dysfunction, and the production of inflammatory cytokines [1,2,3]. Among immune cells infiltrating atherosclerotic lesions, polymorphonuclear neutrophil leukocytes (PMN) have been only recently identified as key contributors to the pathogenesis and progression of ATH [4,5,6], despite their involvement in the chronic, low-grade inflammation occurring early in subjects at high risk to develop cardiovascular disease (CVD) was extensively characterized [7,8,9,10]. PMN infiltration occurs in chronically inflamed arteries, and animal models shows that circulating PMN are recruited into atherosclerotic lesions, while depletion of PMN reduces plaque formation [11]. PMN are the exclusive producers of the enzyme elastase [17], which contribute to matrix degradation and weakening of the vessel wall associated with complications like aneurysm formation and plaque rupture [18]
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