Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model.
Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene beta-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ/apoE(-/-)) developed myocarditis and arteritis after immunization with dendritic cells presenting a beta-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ/apoE(-/-) mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis.
Ludewig
B
B
Institute of Experimental Immunology, Department of Pathology, and Institute for Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland. ludewigb@pathol.unizh.ch
Freigang
S
S
Jäggi
M
M
Kurrer
M O
MO
Pei
Y C
YC
Vlk
L
L
Odermatt
B
B
Zinkernagel
R M
RM
Hengartner
H
H
D000818:Animals; D001011:Aorta / Q000276:immunology* / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D002784:Cholesterol / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006937:Hypercholesterolemia / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011651:Pulmonary Artery / Q000276:immunology* / Q000473:pathology
D002784:Cholesterol