Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensin II-induced progression of established atherosclerosis in hypercholesterolemic mice.
OBJECTIVE
Chronic inflammatory processes might be involved in the progression and destabilization of atherosclerotic plaques. Therefore, identification of the mechanism underlying arterial inflammatory function might lead to the development of novel therapeutic strategies. Angiotensin II (AngII) is implicated in atherogenesis by activating the vascular inflammation system, mainly through monocyte chemotaxis. Therefore, we hypothesized that AngII increases plaque size and promotes destabilization of established atheromas by activating the monocyte chemoattractant protein-1 (MCP-1) pathway.


RESULTS
We report here that 4-week infusion of AngII not only increased plaque size but also induced a destabilization phenotype (ie, increased macrophages and lipids and decreased collagen and smooth muscle cells) of pre-existing atherosclerotic lesions of hypercholesterolemic mice. AngII also enhanced the gene expression of inflammatory cytokines (TNFalpha, IL-6, etc.) and chemokines (MCP-1, CCR2, etc). Blockade of MCP-1, by transfecting the deletion mutant of the human MCP-1 gene into the skeletal muscles, limited AngII-induced progression and destabilization of established atherosclerotic lesions and suppressed the induction of proinflammatory genes.


CONCLUSIONS
These data suggest that MCP-1 functions as a central inflammatory mediator in the AngII-induced progression and changes in plaque composition of established atheroma.
Ni
Weihua
W
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kitamoto
Shiro
S
Ishibashi
Minako
M
Usui
Makoto
M
Inoue
Shujiro
S
Hiasa
Ken-ichi
K
Zhao
Qingwei
Q
Nishida
Ken-ichi
K
Takeshita
Akira
A
Egashira
Kensuke
K
D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D018836:Inflammation Mediators / Q000502:physiology*; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000068557:Olmesartan Medoxomil; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D016037:Single-Blind Method; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D007093:Imidazoles; D018836:Inflammation Mediators; D011993:Recombinant Fusion Proteins; D013777:Tetrazoles; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil