Bone marrow-derived monocyte chemoattractant protein-1 receptor CCR2 is critical in angiotensin II-induced acceleration of atherosclerosis and aneurysm formation in hypercholesterolemic mice.
Angiotensin II (Ang II) is implicated in atherogenesis by activating inflammatory responses in arterial wall cells. Ang II accelerates the atherosclerotic process in hyperlipidemic apoE-/- mice by recruiting and activating monocytes. Monocyte chemoattractant protein-1 (MCP-1) controls monocyte-mediated inflammation through its receptor, CCR2. The roles of leukocyte-derived CCR2 in the Ang II-induced acceleration of the atherosclerotic process, however, are not known. We hypothesized that deficiency of leukocyte-derived CCR2 suppresses Ang II-induced atherosclerosis.


RESULTS
A bone marrow transplantation technique (BMT) was used to develop apoE-/- mice with and without deficiency of CCR2 in leukocytes (BMT-apoE-/-CCR2+/+ and BMT-apoE-/-CCR2-/- mice). Compared with BMT-apoE-/-CCR2+/+ mice, Ang II-induced increases in atherosclerosis plaque size and abdominal aortic aneurysm formation were suppressed in BMT-apoE-/-CCR2-/- mice. This suppression was associated with a marked decrease in monocyte-mediated inflammation and inflammatory cytokine expression.


CONCLUSIONS
Leukocyte-derived CCR2 is critical in Ang II-induced atherosclerosis and abdominal aneurysm formation. The present data suggest that vascular inflammation mediated by CCR2 in leukocytes is a reasonable target of therapy for treatment of atherosclerosis.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Minako
M
Ishibashi
Kensuke
K
Egashira
Qingwei
Q
Zhao
Ken-ichi
K
Hiasa
Kisho
K
Ohtani
Yoshiko
Y
Ihara
Israel F
IF
Charo
Shinobu
S
Kura
Teruhisa
T
Tsuzuki
Akira
A
Takeshita
Kenji
K
Sunagawa
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology*; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000473:pathology*; D001853:Bone Marrow / Q000737:chemistry*; D016026:Bone Marrow Transplantation / Q000379:methods; D007962:Leukocytes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000502:physiology*
D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D000804:Angiotensin II