Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits
Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits
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DOI：
10.1016/s0021-9150(97)00183-4
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发表时间：
1998-01-01
期刊：
影响因子：
5.3
通讯作者：
Frölich, JC
中科院分区：
文献类型：
--
作者：
Böger, RH;Bode-Böger, SM;Frölich, JC
l-精氨酸，内源性一氧化氮（NO）的前体，已被证明可以增强内皮功能并减少胆固醇喂养家兔动脉粥样硬化的进展。在本研究中，我们研究了高胆固醇血症兔主动脉中肌内膜细胞增殖是否增强，以及长期使用l -精氨酸或NO合成酶抑制剂L-NAME是否影响这种增殖反应和血管单核细胞积累。各组分别饲喂1%胆固醇或正常兔粮12周。各组高胆固醇家兔分别口服l-精氨酸（2.25%）或L-NAME （3 mg/dl）饮水。采用核DNA中溴脱氧尿苷（BrdU）掺入的免疫组化检测，定量测定主动脉段肌内膜细胞增殖；使用单克隆抗巨噬细胞/单核细胞抗体（RAM-11）免疫组化评估血管单核细胞积累。采用高效液相色谱法测定血浆中l -精氨酸和内源性NO合成酶抑制剂ADMA的含量。胆固醇喂养增加了主动脉内膜/中膜（I/M）比，这在对照组中是不可测量的，达到1.9 +/- 0.3。这与增强的细胞增殖（胆固醇，2.4 +/- 0.2%;P < 0.05；对照组，每72小时0.02 +/- 0.001% brdu阳性细胞）和血管单核细胞积累相平行。BrdU和α -肌动蛋白双免疫染色显示约2 / 3的增殖细胞为平滑肌细胞。在胆固醇喂养的家兔中，ADMA水平从0.8 +/- 0.1 μ mol/l增加到2.2 +/- 0.2 μ mol/l，但在l-精氨酸或l- name处理下没有变化。肌内膜增殖和内膜/中膜比与ADMA血浆水平相关。饲粮中添加l -精氨酸可使单核细胞积累减少85 +/- 2%（与胆固醇相比P < 0.05）、肌内膜细胞增殖（每72 h 1.8 +/- 0.3%, P < 0.05）和内膜增厚（I/M比0.7 +/- 0.2），而NO合成酶抑制剂L-NAME可使细胞增殖进一步增加至每72 h 3.1 +/- 0.4% （P < 0.05）。胆固醇组和L-NAME组血管单核细胞浸润无显著差异。我们认为，在高胆固醇血症的兔主动脉中，细胞增殖和血管单核细胞积累增强。这些致动脉粥样硬化作用可以通过饮食中的l -精氨酸来减轻。一氧化氮形成减少可能是高胆固醇血症兔主动脉单核细胞积累和细胞增殖增强的基础。观察到的细胞增殖抑制增加了我们对l -精氨酸在体内抗动脉粥样硬化作用的理解。(C) 1998爱思唯尔科学爱尔兰有限公司
L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce the progression of atherosclerosis in cholesterol-fed rabbits. In the present study, we investigated whether myointimal cell proliferation is enhanced in hypercholesterolaemic rabbit aorta and whether chronic treatment of the rabbits with L-arginine or with the NO synthase inhibitor L-NAME influences this proliferative response and vascular monocyte accumulation. Rabbits were fed 1% cholesterol or normal rabbit chow for 12 weeks. Subgroups of cholesterol-fed rabbits were treated with oral L-arginine (2.25%) or L-NAME (3 mg/dl) in drinking water. Myointimal cell proliferation was quantified in aortic segments by immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation into nuclear DNA; vascular monocyte accumulation was assessed by immunohistochemistry using a monoclonal anti-macrophage/monocyte antibody (RAM-11). Plasma levels of L-arginine and the endogenous NO synthase inhibitor, ADMA, were quantified by high-performance liquid chromatography (HPLC). Cholesterol feeding increased the aortic intima/media (I/M) ratio, which was not measurable in the control group, to 1.9 +/- 0.3. This was paralleled by enhanced cell proliferation (cholesterol, 2.4 +/- 0.2%; P < 0.05; control, 0.02 +/- 0.001% BrdU-positive cells per 72 h) and vascular monocyte accumulation. Double immunostaining for BrdU and alpha-actin showed that about two thirds of the proliferating cells were smooth muscle cells. ADMA levels increased from 0.8 +/- 0.1 mu mol/l to 2.2 +/- 0.2 mu mol/l in cholesterol-fed rabbits, but were unchanged by L-arginine or L-NAME treatment. Myointimal proliferation and intima/media ratios were correlated with ADMA plasma levels. Dietary L-arginine reduced monocyte accumulation by 85 +/- 2% (P < 0.05 vs cholesterol), myointimal cell proliferation (1.8 +/- 0.3% per 72 h; P < 0.05) and intimal thickening (I/M ratio: 0.7 +/- 0.2), whereas the inhibitor of NO synthase, L-NAME, further increased cell proliferation to 3.1 +/- 0.4% per 72 h (P < 0.05). No significant difference was observed in vascular monocyte infiltration between the cholesterol and L-NAME groups. We conclude that cell proliferation and vascular monocyte accumulation are enhanced in hypercholesterolaemic rabbit aorta. These atherogenic effects can be attenuated by dietary L-arginine. Decreased NO formation might underlie the enhanced monocyte accumulation and cell proliferation in hypercholesterolaemic rabbit aorta. The observed inhibition of cell proliferation adds to our understanding of the antiatherosclerotic effects of L-arginine in vivo. (C) 1998 Elsevier Science Ireland Ltd.