Systemic inflammation in primary hypercholesterolemia results in platelet and leukocyte activation and their enhanced endothelial adhesiveness

[Speaker] Aida Collado:1
[Co-author] Patrice Marques:2, Elena Domingo:1, Eva Perello:3, Jose Tomas Real:2,3,4,5, Laura Piqueras:2, Juan Francisco Ascaso:2,3,4,5, Maria Jesus Sanz:1,2
1:Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain, 2:Institute of Health Research INCLIVA, Valencia, Spain, 3:Endocrinology and Nutrition Unit, University Clinic Hospital, Valencia, Spain, 4:Department of Medicine, Faculty of Medicine, University of Valencia, Spain, 5:CIBERDEM - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, ISCIII, Spain

Background: Primary hypercholesterolemia (PH) is an autosomal dominant monogenic disease of lipoproteic metabolism characterized by a marked increase of low-density lipoprotein (LDL) levels. A low grade of systemic inflammation is often associated with PH and systemic inflammation is involved in the development of premature coronary diseases associated with the atherosclerotic process.
Objective: Since immune cells play a key role in atherogenesis and the progression of the atherosclerotic plaque, we have investigated the activation state of different immune players in PH and their potential consequences in the development of cardiovascular disorders.
Methods: Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine platelet activation (P-selectin expression and circulating PAC-1+ platelets), leukocyte activation (CD69 expression) and the percentage of circulating platelet-leukocyte aggregates. Functional studies were performed in the parallel-plate flow chamber assay to evaluate platelet-leukocyte and leukocyte adhesiveness to TNFα-unstimulated or stimulated (20 ng/ml, 24h) arterial endothelium.
Results: PH patients presented greater numbers of activated circulating platelets (PAC-1+) with increased P-selectin expression than age-matched controls. Interestingly, the percentage of circulating eosinophils, type 3 monocytes, Th2 and Th17 lymphocytes was significantly increased in patients with PH compared with the respective control group. In addition, the pathological state was associated with higher percentages of circulating platelet-granulocyte, platelet-monocyte (types 1 and 3) and platelet-lymphocyte (Th1, Th2, Th17 and CD8+) aggregates than the healthy volunteers. Furthermore, all the leukocyte subsets investigated showed increased activation state in PH patients than in age-matched controls. This resulted in increased platelet-leukocyte and leukocyte adhesiveness to the unstimulated (functional) or TNFα-stimulated (dysfunctional) arterial endothelium in PH patients compared with that found in the age-matched controls.
Conclusion: We have provided evidence that increased platelet and leukocyte activation in PH patients leads to enhanced arterial leukocyte adhesiveness. Therefore, since platelet/leukocyte- and leukocyte-arterial adhesion precedes atherogenic process development, it is plausible that the activation state of these immune players may predict the likelihood of suffering further cardiovascular events in PH patients.
Funding: SAF2011-23777, SAF2014-57845R, CPII13/00025, PI15/00082, PIE15/00013, GVACOMP2014-006 and PROMETEO II/2013/014 from Spanish Ministry of Economy and Competiveness, ISCIII, European Regional Development Fund and Generalitat Valenciana.
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