Silencing of either SR-A or CD36 reduces atherosclerosis in hyperlipidaemic mice and reveals reciprocal upregulation of these receptors.
OBJECTIVE
Macrophage scavenger receptor A (SR-A) and class B scavenger receptor CD36 (CD36) contribute to foam cell formation and atherogenesis via uptake of modified lipoproteins. So far, the role of these scavenger receptors has been studied mainly using knockout models totally lacking these receptors. We studied the role of SR-A and CD36 in foam cell formation and atherogenesis by RNA interference (RNAi)-mediated silencing, which is a clinically feasible method to down-regulate the expression of these receptors.


RESULTS
We constructed lentivirus vectors encoding short hairpin RNAs (shRNAs) against mouse SR-A and CD36. Decreased SR-A but not CD36 expression led to reduced foam cell formation caused by acetylated low-density lipoprotein (LDL) in mouse macrophages, whereas the uptake of oxidized LDL was not altered. More importantly, silencing of SR-A upregulates CD36 and vice versa. In LDL receptor-deficient apolipoprotein B100 (LDLR(-/-)ApoB(100/100)) mice kept on a western diet, silencing of either SR-A or CD36 in bone marrow cells led to a marked decrease (37.4 and 34.2%, respectively) in cross-sectional lesion area, whereas simultaneous silencing of both receptors was not effective.


CONCLUSIONS
Our results suggest that silencing of either SR-A or CD36 alone reduces atherogenesis in mice. However, due to reciprocal upregulation, silencing of both SR-A and CD36 is not effective.
Mäkinen
Petri I
PI
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Lappalainen
Jari P
JP
Heinonen
Suvi E
SE
Leppänen
Pia
P
Lähteenvuo
Markku T
MT
Aarnio
Jussi V
JV
Heikkilä
Janne
J
Turunen
Mikko P
MP
Ylä-Herttuala
Seppo
S
D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018955:CD36 Antigens / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D001055:Apolipoproteins B; D018955:CD36 Antigens; D011973:Receptors, LDL; D051117:Scavenger Receptors, Class A