Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation.
Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation.
复制标题
轻度氧化的低密度脂蛋白与血管紧张素II协同作用，诱导血管平滑肌细胞增殖。
DOI：
10.1097/00004872-200106000-00011
复制
发表时间：
2001
影响因子：
4.9
通讯作者：
Benedict,CR
中科院分区：
文献类型：
--
作者：
Watanabe,T;Pakala,R;Katagiri,T;Benedict,CR
目的轻度氧化低密度脂蛋白（mox-LDL）和高度氧化低密度脂蛋白（ox-LDL）作为心血管疾病的重要危险因素已引起广泛关注。此外，血管紧张素II（Ang II）似乎在高血压和动脉粥样硬化的发展中起着至关重要的作用。我们评估了氧化修饰的LDL及其主要氧化成分，即过氧化氢（H2 O2），溶血磷脂酰胆碱（LPC），和4-羟基-2-壬烯醛（HNE）和他们的相互作用与血管紧张素Ⅱ对血管平滑肌细胞（VSMC）的DNA合成的影响方法：生长停滞的兔VSMC在无血清培养基中孵育不同浓度的天然LDL，mox-LDL，ox-LDL，H2 O2，LPC，或HNE与或不与血管紧张素Ⅱ。结果：Ang Ⅱ呈剂量依赖性地刺激VSMCs DNA合成，在1 μmol/l浓度时作用最大（173%）。Ang II（0.5 μmol/l）可放大500 ng/ml天然LDL、100 ng/ml ox-LDL和50 ng/ml mox-LDL对DNA合成的影响（分别为108 - 234%、124 - 399%、129 - 433%）。H2 O2浓度为5 μmol/l时，作用最大（177%），LPC浓度为15 μmol/l时，作用最大（156%），HNE浓度为0.5 μmol/l时，作用最大（137%）。低浓度的H2 O2（1 μmol/l）、LPC（5 μmol/l）或HNE（0.1 μmol/l）与Ang Ⅱ（0.5 μmol/l）也可协同诱导DNA合成，分别为308、304或238%。血管紧张素II的协同作用（0.5 μmol/l）与mox-LDL、ox-LDL（均为50 ng/ml）、H2 O2（1 μmol/l），LPC（5 μmol/l）或HNE普罗布考（0.1 μmol/l）对DNA合成的抑制作用可完全逆转（10 μmol/l），一种有效的抗氧化剂和坎地沙坦结论mox LDL、ox LDL及其主要成分H2 O2、LPC、HNE与Ang Ⅱ协同诱导VSMC DNA合成。抗氧化剂与AT 1受体阻断剂的组合可能有效地治疗与高血压和动脉粥样硬化相关的VSMC增殖性疾病。
ObjectivesConsiderable attention has been focused on both mildly oxidized low-density lipoprotein (mox-LDL) and highly oxidized LDL (ox-LDL) as important risk factors for cardiovascular disease. Further, angiotensin II (Ang II) appears to play a crucial role in the development of hypertension and atherosclerosis. We assessed the effect of oxidatively modified LDL and its major oxidative components, ie, hydrogen peroxide (H 2 O 2), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) and their interaction with Ang II on vascular smooth muscle cell (VSMC) DNA synthesis.Methods:Growth-arrested rabbit VSMCs were incubated in serum-free medium with different concentrations of native LDL, mox-LDL, ox-LDL, H 2 O 2, LPC, or HNE with or without Ang II. DNA synthesis in VSMCs was measured by [3 H] thymidine incorporation.Results:Ang II stimulated DNA synthesis in a dose-dependent manner with a maximal effect at a concentration of 1 μmol/l (173%). Ang II (0.5 μmol/l) amplified the effect of native LDL at 500 ng/ml, ox-LDL at 100 ng/ml, and mox-LDL at 50 ng/ml on DNA synthesis (108 to 234%, 124 to 399%, 129 to 433%, respectively). H 2 O 2 had a maximal effect at a concentration of 5 μmol/l (177%), LPC at 15 μmol/l (156%), and HNE at 0.5 μmol/l (137%). Low concentrations of H 2 O 2 (1 μmol/l), LPC (5 μmol/l), or HNE (0.1 μmol/l) also acted synergisitically with Ang II (0.5 μmol/l) in inducing DNA synthesis to 308, 304, or 238%, respectively. Synergistic interactions of Ang II (0.5 μmol/l) with mox-LDL, ox-LDL (both 50 ng/ml), H 2 O 2 (1 μmol/l), LPC (5 μmol/l), or HNE (0.1 μmol/l) on DNA synthesis were completely reversed by the combined use of probucol (10 μmol/l), a potent antioxidant and candesartan (0.1 μmol/l), an AT 1 receptor antagonist.ConclusionsOur results suggest that mox-LDL, ox-LDL, and their major components H 2 O 2, LPC, and HNE act synergistically with Ang II in inducing VSMC DNA synthesis. A combination of antioxidants with AT 1 receptor blockade may be effective in the treatment of VSMC proliferative disorders associated with hypertension and atherosclerosis.