INTRODUCTION/HYPOTHESIS:
Leukocytes are a major component of atherosclerotic plaques, drive plaque progression and are continuously recruited from the blood. The leukocyte adhesion molecules VCAM-1, ICAM-1/2 and E-/P-Selectin are expressed on plaque endothelial cells and are the key players in this recruitment process. We here present a novel therapeutic approach that targets leukocyte recruitment to plaques.
METHODS:
We tested a nanoparticle system that effectively delivered short interfering RNAs targeting VCAM-1, ICAM-1/2 and E-/P-Selectin simultaneously (siCAM5) to endothelial cells of atherosclerosis prone ApoE-/- mice and C57BL/6J mice after myocardial infarction (permanent coronary ligation) and assessed leukocyte recruitment/content and plaque phenotype by flow cytometry, histology, qPCR and fluorescence molecular tomography/computed tomography imaging.
RESULTS:
Efficient degradation of VCAM-1, ICAM-1/2 and E-/P-Selectin on endothelial cells attenuated neutrophil and monocyte numbers in infarcts and atherosclerotic plaques (neutrophil numbers, siControl 10,974±1,250 vs. siCAM5 6,963±1,077, p<0.05; Ly6Chigh monocyte numbers, siControl 6,044±1,212 vs. siCAM5 3,770±293, p<0.05), reduced levels of pro-inflammatory cytokines in plaques, decreased protease activity in plaques (protease activity in pmol, siControl 49.4±2.8 vs. siCAM5 35.9±3.0, p<0.01), and resulted in a less inflammatory plaque phenotype (necrotic core mm2/aortic root, siControl 0.09±0.01 vs. siCAM5 0.05±0.01, p<0.05; fibrous cap μm/aortic root, siControl 36.7±9.5 vs. siCAM5 63.1±5.4, p<0.05) and lower numbers of plaque macrophages (siControl 30,313±4,414 vs. siCAM5 17,198±2,070, p<0.01).
CONCLUSIONS:
Taken together, the described approach can successfully suppress leukocyte recruitment to atherosclerotic plaques and infarcted hearts. It may allow aggressive medical interventions in patients with inflammatory atherosclerosis.
Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells.