Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle–Like Progenitor Cells
Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle–Like Progenitor Cells
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DOI：
10.1161/atvbaha.107.147124
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发表时间：
2007-11
期刊：
影响因子：
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通讯作者：
Takaaki Yamada;T. Kondo;Y. Numaguchi;M. Tsuzuki;T. Matsubara;I. Manabe;M. Sata;R. Nagai;T. Murohara
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文献类型：
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作者：
Takaaki Yamada;T. Kondo;Y. Numaguchi;M. Tsuzuki;T. Matsubara;I. Manabe;M. Sata;R. Nagai;T. Murohara
目的：血管紧张素II（ATII）1型受体（AT 1 R）阻滞剂（ARB）已被证明可抑制新生内膜形成。骨髓来源的单个核细胞（BM-MNCs）在损伤的动脉壁产生平滑肌（SM）样细胞，并有助于新生内膜形成。然而，在新生内膜形成过程中，肾素-血管紧张素系统在SM样细胞归巢过程中的作用尚不清楚。材料和方法-当人BM-MNCs和外周血MNCs（PB-MNCs）在PDGF-BB和bFGF处理下培养时，这些细胞产生表达SMA、SMemb和SM 1蛋白的SM样细胞。RT-PCR显示AT 1 R、ATII 2型受体（AT 2 R）、SMA和SMemb mRNA的表达。ATII可促进SM-like细胞的分化，而ARB CV11974可抑制ATII诱导的SM-like细胞分化（P<0.05）。然后，我们研究了ATII，CV11974和AT 2 R拮抗剂PD 123319对体内损伤动脉新生内膜形成和BM衍生的SM样细胞掺入的影响。将来自绿色荧光蛋白（GFP）转基因小鼠的BM移植到经辐照的WT小鼠中。GFP-BM嵌合体小鼠在左股动脉上经受线损伤。ATII（100 ng/kg/min）刺激，而CV11974（1 mg/kg/d）抑制新生内膜形成。新生内膜GFP+SMA+细胞数与内膜/中膜比值呈显著正相关（r=0.69，P<0.05）。结论骨髓来源的SM样祖细胞参与了动脉损伤后内膜的形成。ATII加速了这一过程，而ARB抑制了这一过程。这些是ARB介导的抑制动脉粥样硬化疾病进展的新方面。
Objectives—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. Material and 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 SMA, SMemb, and SM1 proteins. RT-PCR showed the expression of AT1R, ATII type 2 receptor (AT2R), SMA, 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+SMA+ cells at neointima correlated with the intima/media ratio (r=0.69, P<0.05). Conclusion—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.