Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling.
Activated monocytes are present in the arterial walls of hypertensive patients and animals. Monocyte chemoattractant protein-1 (MCP-1), which controls monocyte function through its receptor (CCR2), is implicated in hypertensive inflammatory changes in the arterial wall. The role of CCR2 expression on monocytes in hypertension-induced vascular remodeling, however, has not been addressed. We hypothesized that CCR2 on monocytes is critical in hypertension-induced vascular inflammation and remodeling. Hypertension was induced by infusion of angiotensin II (Ang II) into wild-type mice, CCR2-deficient (CCR2-/-) mice, and bone marrow-transferred mice with a leukocyte-selective CCR2 deficiency (BMT-CCR2-/-). In wild-type mice, Ang II increased CCR2 intensity in circulating monocytes, which was prevented by an Ang II type-1 (AT1) receptor blocker or blunted in AT1 receptor-deficient mice. Enhanced CCR2 intensity on monocytes was observed in hypertensive patients and rats, and was reduced by treatment with the Ang II receptor blocker, supporting the clinical relevance of the observation in mice. In CCR2-/- and BMT-CCR2-/- mice, Ang II-induced vascular inflammation and vascular remodeling (aortic wall thickening and fibrosis) were blunted as compared with control mice. In contrast, Ang II-induced left ventricular hypertrophy developed in CCR2-/- and BMT-CCR2-/- mice. The present study suggests that CCR2 expression in monocytes has a critical role in vascular inflammation and remodeling in Ang II-induced hypertension, and possibly in other forms of hypertension.
Ishibashi
Minako
M
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Hiasa
Ken-ichi
K
Zhao
Qingwei
Q
Inoue
Shujiro
S
Ohtani
Kisho
K
Kitamoto
Shiro
S
Tsuchihashi
Miyuki
M
Sugaya
Takeshi
T
Charo
Israel F
IF
Kura
Shinobu
S
Tsuzuki
Teruhisa
T
Ishibashi
Tatsuro
T
Takeshita
Akira
A
Egashira
Kensuke
K
D000804:Angiotensin II / Q000633:toxicity; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000068557:Olmesartan Medoxomil; D010865:Pilot Projects; D011828:Radiation Chimera; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D013777:Tetrazoles; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester