Angiotensin II receptor blocker inhibits neointimal hyperplasia through regulation of smooth muscle-like progenitor cells.
OBJECTIVE
Angiotensin II (ATII) type 1 receptor (AT1R) blocker (ARB) has been shown to inhibit neointimal formation. Bone marrow-derived mononuclear cells (BM-MNCs) give rise to smooth muscle (SM)-like cells at injured arterial wall and contribute to neointimal formation. However, role of the renin-angiotensin system in the homing process of SM-like cells during neointimal formation is unknown.


METHODS
When human BM-MNCs and peripheral blood MNCs (PB-MNCs) were cultured under treatment with PDGF-BB and bFGF, these cells gave rise to SM-like cells with expression of alphaSMA, SMemb, and SM1 proteins. RT-PCR showed the expression of AT1R, ATII type 2 receptor (AT2R), alphaSMA, and SMemb mRNAs. ATII accelerated the differentiation of SM-like cells, which was inhibited by an ARB CV11974 (P<0.05). We then examined the effects of ATII, CV11974, and AT2R antagonist PD123319 on neointimal formation and BM-derived SM-like cell incorporation at injured arteries in vivo. BM from green fluorescence protein (GFP)-transgenic mice was transplanted to irradiated WT mice. GFP-BM chimera mice were subjected to wire injury on the left femoral artery. ATII (100 ng/kg/min) stimulated whereas CV11974 (1 mg/kg/d) inhibited neointimal formation. Number of GFP+ alphaSMA+ cells at neointima correlated with the intima/media ratio (r=0.69, P<0.05).


CONCLUSIONS
BM-derived SM-like progenitor cells contributed to the neointimal formation after arterial injury. ATII accelerated whereas ARB suppressed this process. These are new aspects of the ARB-mediated inhibition of atherosclerotic disease progression.
Yamada
Takaaki
T
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya 466-8550, Japan.
Kondo
Takahisa
T
Numaguchi
Yasushi
Y
Tsuzuki
Michitaka
M
Matsubara
Tatsuaki
T
Manabe
Ichiro
I
Sata
Masataka
M
Nagai
Ryozo
R
Murohara
Toyoaki
T
D000804:Angiotensin II / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D016491:Peripheral Vascular Diseases / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D000804:Angiotensin II; C073402:PD 123319