Deletion of L-Selectin Increases Atherosclerosis Development in ApoE−/− Mice

Abstract

Atherosclerosis is an inflammatory disease characterized by accumulation of leukocytes in the arterial intima. Members of the selectin family of adhesion molecules are important mediators of leukocyte extravasation. However, it is unclear whether L-selectin (L-sel) is involved in the pathogenesis of atherosclerosis. In the present study, mice deficient in L-selectin (L-sel −/−) animals were crossed with mice lacking Apolipoprotein E (ApoE −/−). The development of atherosclerosis was analyzed in double-knockout ApoE/L-sel (ApoE −/− L-sel −/−) mice and the corresponding ApoE −/− controls fed either a normal or a high cholesterol diet (HCD). After 6 weeks of HCD, aortic lesions were increased two-fold in ApoE −/− L-sel −/− mice as compared to ApoE −/− controls (2.46%±0.54% vs 1.28%±0.24% of total aortic area; p<0.05). Formation of atherosclerotic lesions was also enhanced in 6-month-old ApoE −/− L-sel −/− animals fed a normal diet (10.45%±2.58% vs 1.87%±0.37%; p<0.05). In contrast, after 12 weeks of HCD, there was no difference in atheroma formation between ApoE −/− L-sel −/− and ApoE −/− mice. Serum cholesterol levels remained unchanged by L-sel deletion. Atherosclerotic plaques did not exhibit any differences in cellular composition assessed by immunohistochemistry for CD68, CD3, CD4, and CD8 in ApoE −/− L-sel −/− as compared to ApoE −/− mice. Leukocyte rolling on lesions in the aorta was similar in ApoE −/− L-sel −/− and ApoE −/− animals. ApoE −/− L-sel −/− mice exhibited reduced size and cellularity of peripheral lymph nodes, increased size of spleen, and increased number of peripheral lymphocytes as compared to ApoE −/− controls. These data indicate that L-sel does not promote atherosclerotic lesion formation and suggest that it rather protects from early atherosclerosis.

Plasma and serum L-selectin and clinical and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA)

“…Finally, the inclusion of subclinical endpoints allowed us to investigate the role of L-selectin in early atherosclerosis, as suggested by previous animal models. 4 We acknowledge limitations of this study. The number of clinical events in each ethnic group might not be sufficient to observe ethnic-specific associations of CVD events with soluble L-selectin.…”

“…Previous studies in vivo suggested a facilitating role of the membrane-bound form of this adhesion protein in leukocyte accumulation during atherogenesis; 24,25 on the contrary, in animal models of atherosclerosis lacking L-selectin, a protective role of the protein during early phases of plaque formation was observed. 4 The soluble portion of L-selectin, formed by protease shedding, is easily measurable in serum or plasma, but its specific function in atherosclerosis is difficult to interpret. In fact, circulating L-selectin was found to be protective in some studies, 7–9 and a risk factor in others.…”

“…While a protective role of the cell-bound portion of this protein has been demonstrated in animal models, 4 human studies investigating circulating L-selectin and cardiovascular disease (CVD) are inconsistent. The later appear to be complicated by whether the protein was measured in serum or plasma samples.…”

Glycosyltransferases, glycosylation and atherosclerosis

“…Conversely, L-selectin is constitutively expressed on leukocytes. L-selectin deficiency increases size, but does not change cellular composition in atherosclerotic lesions [29], suggesting that L-selectin protects from early atherosclerosis. Therefore, three selectins mediate leukocyte rolling on inflammatory sites, but not all selectins promote atherogenesis, indicating that there exist distinct effects to three selectins.…”

Pathomorphism of Limb Major Vessels in Experimental Atherogenic Inflammation. The Role of Adventitial Intimal Relations (Review)

“…Impaired expression balance of pro-atherogenic (proinflammatory) and anti-atherogenic (anti-inflammatory) cell markers if hyperlipidemia conditions are preserved stabilize destruction in subendothelial space. The expression of blood residual cell receptors under vascular endothelium and of vascular endothelium itself, namely: endothelin-1 [31][32][33][34][35], caveolins-1, -2, and -3 [36, 37], selectins Р (CD62P), Е (CD62E), L (CD62L), and antibodies to them on vascular endothelium, lymphocytes and platelets [38][39][40], intercellular adhesion molecule-1 (ICAM-1) marker [41][42][43], vascular cell adhesion molecule-1 (VCAM-1) marker [44][45][46][47], monocyte chemotactic protein (MCP-1) [48][49][50], macrophage colony-stimulating factor (MCSF) [51][52][53][54][55][56][57], pleiotropic cytokine (TNF-α) [58][59][60][61][62][63][64], С-reactive protein (CRP) [65][66][67][68][69][70], platelet derived growth factor (PDGF) [71][72][73][74][75][76][77], interleukin family in atherosclerosis <...>…”