Pathology of atheromatous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification.
We report comprehensive pathological studies of atheromatous lesions in various inbred mouse strains fed a high-fat, high-cholesterol diet and in two genetically engineered strains that develop spontaneous lesions on a low-fat chow diet. Coronary and aortic lesions were studied with respect to anatomic locations, lesion severity, calcification, and lipofuscin deposition. Surprisingly, the genetic determinants for coronary fatty lesion formation differed in part from those for aortic lesion development. This suggests the existence of genetic factors acting locally as well as systematically in lesion development. We used immunohistochemical analyses to determine the cellular and molecular compositions of the lesions. The aortic lesions contained monocyte/macrophages, lipid, apolipoprotein B, serum amyloid A proteins, and immunoglobulin M and showed expression of vascular cell adhesion molecule-1 and tumor necrosis factor-alpha, all absent in normal arteries. In certain strains, advanced lesions developed in which smooth muscle cells were commonly observed. The lesions in mice targeted for a null mutation in the apolipoprotein E gene were much larger, more widely dispersed, and more fibrous, cellular, and calcified in nature than the lesions in laboratory inbred strains. When apolipoprotein A-II transgenic mice were maintained on a low-fat chow diet, the lesions in these mice were relatively small and located in the very proximal regions of the aorta. There were clear differences in the occurrence of arterial wall calcification among genetically distinct inbred mouse strains, indicating for the first time a genetic component in this clinically significant trait. Analysis of a genetic cross indicated a complex pattern of calcification inheritance with incomplete penetrance.
Qiao
J H
JH
Department of Medicine, University of California, Los Angeles (UCLA), School of Medicine 90024-1679.
Xie
P Z
PZ
Fishbein
M C
MC
Kreuzer
J
J
Drake
T A
TA
Demer
L L
LL
Lusis
A J
AJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D016633:Apolipoprotein A-II / Q000235:genetics; D001055:Apolipoproteins B / Q000032:analysis; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics* / Q000473:pathology; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D003324:Coronary Artery Disease / Q000235:genetics / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D005818:Genetic Engineering; D007075:Immunoglobulin M / Q000032:analysis; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D000685:Serum Amyloid A Protein / Q000032:analysis
D016633:Apolipoprotein A-II; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D007075:Immunoglobulin M; D000685:Serum Amyloid A Protein