Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II.
OBJECTIVE
The role of scavenger receptors in atherogenesis is controversial as a result of conflicting reports and a recent hypothesis suggesting that scavenger receptor absence would enhance the pro-inflammatory, pro-atherogenic milieu. This study addresses the effect of combined absence of scavenger receptors CD36 and SRA I/II on atherosclerosis lesion development in the apolipoprotein E knock-out (apoE degrees ) model.


METHODS
We created background-related strains of apoE degrees , scavenger receptor A I/II knock-out (SRA degrees )/apoE degrees , CD36 knock-out (CD36 degrees )/apoE degrees , and CD36 degrees /SRA degrees /apoE degrees mice that were >99% C57Bl/6. Four-week-old mice were fed a Western diet for 12 weeks and were assessed for lesion burden/morphology, risk factors for atherosclerosis, inflammatory mediators, and macrophage function.


RESULTS
There was a 61 and 74% decrease in total aortic lesion area in CD36 degrees /apoE degrees males and females, respectively, compared with apoE degrees controls. The absence of SRA was protective (32% decrease in lesion) in female mice. The combined absence of CD36 and SRA provided no further protection in either gender. Macrophages from mice lacking CD36 had decreased pro-inflammatory characteristics and less migration to a pro-inflammatory stimulus. Plasma levels of cytokines/chemokines showed that CD36 degrees /apoE degrees and CD36 degrees /SRA degrees /apoE degrees mice had a less pro-inflammatory phenotype compared with apoE degrees and SRA degrees /apoE degrees mice. Oblivious mice in the apoE degrees background ruled out potential 'passenger gene' effects in the case of CD36.


CONCLUSIONS
These results provide new insights into the pro-atherogenic mechanisms of CD36 by implicating processes other than modified lipoprotein uptake.
Department of Cell Biology, Cleveland Clinic, 9500 Euclid Ave., NC-10, Cleveland, OH 44195, USA.
Sai
S
Kuchibhotla
Difernando
D
Vanegas
David J
DJ
Kennedy
Ella
E
Guy
George
G
Nimako
Richard E
RE
Morton
Maria
M
Febbraio
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001786:Blood Glucose / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D001786:Blood Glucose; D018955:CD36 Antigens; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D051117:Scavenger Receptors, Class A; D014280:Triglycerides; D002784:Cholesterol