Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosis.
OBJECTIVE
In dyslipidemic states, platelets become hyperreactive, secreting molecules that promote atherosclerosis. We have shown that the semaphorin family member, sema4D (CD100), is expressed on the surface of platelets and proposed that its role includes promoting thrombus growth by binding to nearby platelets and endothelial cells, both of which express sema4D receptors. Here we tested the hypothesis that deleting sema4D will attenuate the adverse consequences of dyslipidemia on platelets and the vessel wall.


RESULTS
Platelet function and atherosclerotic lesion formation were measured in LDLR(-/-) and sema4D(-/-)LDLR(-/-) mice after 6 months on a high-fat diet. All of the mice developed the dyslipidemia expected on this diet in the absence of functional LDL receptors. However, when compared to LDLR(-/-) mice, sema4D(-/-) LDLR(-/-) mice had reduced lipid deposition in the descending aorta, a 6-fold decrease in the frequency of arterial occlusion and a reduction to near wild-type levels in the accumulation of platelets after injury. These differences were retained ex vivo, with a marked decrease in platelet accumulation on collagen under flow and in platelet aggregation.


CONCLUSIONS
These results show that loss of sema4D expression reduces the platelet hyperactivity otherwise found in dyslipidemia, and confers protection against the development of atherosclerosis.
Zhu
Li
L
Department of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Stalker
Timothy J
TJ
Fong
Karen P
KP
Jiang
Hong
H
Tran
Anh
A
Crichton
Irene
I
Lee
Eric K
EK
Neeves
Keith B
KB
Maloney
Sean F
SF
Kikutani
Hitoshi
H
Kumanogoh
Atsushi
A
Pure
Ellen
E
Diamond
Scott L
SL
Brass
Lawrence F
LF
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001013:Aorta, Thoracic / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D004036:Diet, Atherogenic; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000502:physiology*; D039961:Semaphorins / Q000502:physiology*; D013927:Thrombosis / Q000503:physiopathology
D015703:Antigens, CD; C093224:CD100 antigen; D039961:Semaphorins