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P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice.

Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL - J. Exp. Med. (2000)

Bottom Line: An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001.The reduction in lesion area for the E-selectin mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01).These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

ABSTRACT
The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

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Histopathologic comparison of aortas from study animals. Sections shown are typical of the most advanced lesions found in animals of each genotype. (A) C57BL/6 wild-type murine aorta with intact intimal (top), unremarkable media (middle), and adventitial (bottom) layers with no evidence of atheromatous lesion. (B) Aorta from apo E−/− mouse with no CAM deficiency showing well formed atheromatous plaque characterized by foam cells, cell debris, cholesterol clefts, and calcification (arrow) within the expanded intima. Lesions exhibiting the calcification seen only in very advanced lesions were only found in apo E−/− mice with no CAM deficiency. (C) Aorta from an apo E−/−ICAM-1−/− animal with lesion composed of foam cells, cholesterol clefts, and extracellular lipid in expanded intima (arrow). (D) Aorta from apo E−/− P-selectin−/− animal with less developed atherosclerotic lesions (arrows) composed of frequent foam cells within expanded intima. Note relatively normal aortic segment between atheromatous lesions. (All hematoxylin and eosin stain with original magnification of 200).
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Figure 3: Histopathologic comparison of aortas from study animals. Sections shown are typical of the most advanced lesions found in animals of each genotype. (A) C57BL/6 wild-type murine aorta with intact intimal (top), unremarkable media (middle), and adventitial (bottom) layers with no evidence of atheromatous lesion. (B) Aorta from apo E−/− mouse with no CAM deficiency showing well formed atheromatous plaque characterized by foam cells, cell debris, cholesterol clefts, and calcification (arrow) within the expanded intima. Lesions exhibiting the calcification seen only in very advanced lesions were only found in apo E−/− mice with no CAM deficiency. (C) Aorta from an apo E−/−ICAM-1−/− animal with lesion composed of foam cells, cholesterol clefts, and extracellular lipid in expanded intima (arrow). (D) Aorta from apo E−/− P-selectin−/− animal with less developed atherosclerotic lesions (arrows) composed of frequent foam cells within expanded intima. Note relatively normal aortic segment between atheromatous lesions. (All hematoxylin and eosin stain with original magnification of 200).

Mentions: Atherosclerotic lesions are more likely to be observed in specific areas of the aorta. These include the valve cusps, aortic arch, and the abdominal aorta in the region of the renal arteries ( Fig. 2). Smaller lesions including fatty streaks were seen throughout the aorta but were more common at arterial branch points. Cross-sections of the most advanced lesions found in C57BL/6 wild-type, apo E−/− with no CAM deficiency, apo E−/−ICAM-1−/−, and apo E−/−P-selectin−/− mice are shown in Fig. 3. The calcification seen in the advanced lesions of apo E−/− mice was not observed in any of the aortas analyzed from ICAM-1 or P-selectin mice. The most advanced lesions seen in the P-selectin−/− mice contained foam cells within expanded intima.


P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice.

Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL - J. Exp. Med. (2000)

Histopathologic comparison of aortas from study animals. Sections shown are typical of the most advanced lesions found in animals of each genotype. (A) C57BL/6 wild-type murine aorta with intact intimal (top), unremarkable media (middle), and adventitial (bottom) layers with no evidence of atheromatous lesion. (B) Aorta from apo E−/− mouse with no CAM deficiency showing well formed atheromatous plaque characterized by foam cells, cell debris, cholesterol clefts, and calcification (arrow) within the expanded intima. Lesions exhibiting the calcification seen only in very advanced lesions were only found in apo E−/− mice with no CAM deficiency. (C) Aorta from an apo E−/−ICAM-1−/− animal with lesion composed of foam cells, cholesterol clefts, and extracellular lipid in expanded intima (arrow). (D) Aorta from apo E−/− P-selectin−/− animal with less developed atherosclerotic lesions (arrows) composed of frequent foam cells within expanded intima. Note relatively normal aortic segment between atheromatous lesions. (All hematoxylin and eosin stain with original magnification of 200).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195808&req=5

Figure 3: Histopathologic comparison of aortas from study animals. Sections shown are typical of the most advanced lesions found in animals of each genotype. (A) C57BL/6 wild-type murine aorta with intact intimal (top), unremarkable media (middle), and adventitial (bottom) layers with no evidence of atheromatous lesion. (B) Aorta from apo E−/− mouse with no CAM deficiency showing well formed atheromatous plaque characterized by foam cells, cell debris, cholesterol clefts, and calcification (arrow) within the expanded intima. Lesions exhibiting the calcification seen only in very advanced lesions were only found in apo E−/− mice with no CAM deficiency. (C) Aorta from an apo E−/−ICAM-1−/− animal with lesion composed of foam cells, cholesterol clefts, and extracellular lipid in expanded intima (arrow). (D) Aorta from apo E−/− P-selectin−/− animal with less developed atherosclerotic lesions (arrows) composed of frequent foam cells within expanded intima. Note relatively normal aortic segment between atheromatous lesions. (All hematoxylin and eosin stain with original magnification of 200).
Mentions: Atherosclerotic lesions are more likely to be observed in specific areas of the aorta. These include the valve cusps, aortic arch, and the abdominal aorta in the region of the renal arteries ( Fig. 2). Smaller lesions including fatty streaks were seen throughout the aorta but were more common at arterial branch points. Cross-sections of the most advanced lesions found in C57BL/6 wild-type, apo E−/− with no CAM deficiency, apo E−/−ICAM-1−/−, and apo E−/−P-selectin−/− mice are shown in Fig. 3. The calcification seen in the advanced lesions of apo E−/− mice was not observed in any of the aortas analyzed from ICAM-1 or P-selectin mice. The most advanced lesions seen in the P-selectin−/− mice contained foam cells within expanded intima.

Bottom Line: An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001.The reduction in lesion area for the E-selectin mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01).These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

ABSTRACT
The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

Show MeSH
Related in: MedlinePlus