Watanabe T, Pakala R, Katagiri T, Benedict C R
Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Health Science Center, Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Circulation. 2001 Jul 3;104(1):16-8. doi: 10.1161/hc2601.092848.
The urotensin II (UII) found in coronary atheroma is the most potent vasoconstrictor known to date. Mildly oxidized LDL (moxLDL) contributes to atherogenesis and plaque formation. We assessed the effect of UII and its interaction with moxLDL and the oxidative components of moxLDL on vascular smooth muscle cell (VSMC) proliferation. Methods and Results-Growth-arrested VSMCs were incubated in serum-free medium with different concentrations of LDL, moxLDL, oxLDL, hydrogen peroxide, lysophosphatidylcholine, or 4-hydroxy-2-nonenal, with or without UII. [(3)H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. UII stimulated [(3)H]thymidine incorporation in a dose-dependent manner, with a maximal effect at a concentration of 50 nmol/L (161%). Low concentrations of UII potentiated the mitogenic effect of LDL (108% to 242%), oxLDL (129% to 302%), moxLDL (120% to 337%), hydrogen peroxide (177% to 226%), lysophosphatidylcholine (115% to 332%), and 4-hydroxy-2-nonenal (142% to 299%). The synergistic interaction between UII and moxLDL was partially inhibited by anti-Gq/11alpha antibody, the epidermal growth factor receptor tyrosine kinase inhibitor erbstatin A (10 micromol/L), and the intracellular free radical scavenger N-acetylcysteine (400 micromol/L) and was completely inhibited by the c-Src tyrosine kinase inhibitor radicicol (10 micromol/L), the protein kinase C (PKC) inhibitor Ro31-8220 (0.1 micromol/L), and the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 micromol/L).
Our results suggest that UII acts synergistically with moxLDL in inducing VSMC proliferation via the c-Src/PKC/MAPK pathway, which may explain the relatively rapid progression of atherosclerosis in patients with hypertension and hypercholesterolemia.
在冠状动脉粥样硬化斑块中发现的尾加压素II（UII）是迄今为止已知的最有效的血管收缩剂。轻度氧化的低密度脂蛋白（moxLDL）促进动脉粥样硬化的发生和斑块形成。我们评估了UII及其与moxLDL以及moxLDL氧化成分对血管平滑肌细胞（VSMC）增殖的影响。
将生长停滞的VSMC在无血清培养基中与不同浓度的低密度脂蛋白（LDL）、moxLDL、氧化型低密度脂蛋白（oxLDL）、过氧化氢、溶血磷脂酰胆碱或4-羟基-2-壬烯醛一起孵育，同时或不同时加入UII。将[³H]胸苷掺入DNA的量作为VSMC增殖的指标进行测定。UII以剂量依赖的方式刺激[³H]胸苷掺入，在浓度为50 nmol/L时达到最大效应（161%）。低浓度的UII增强了LDL（108%至242%）、oxLDL（129%至302%）、moxLDL（120%至337%）、过氧化氢（177%至226%）、溶血磷脂酰胆碱（115%至332%）和4-羟基-2-壬烯醛（142%至299%）的促有丝分裂作用。UII与moxLDL之间的协同相互作用被抗Gq/11α抗体、表皮生长因子受体酪氨酸激酶抑制剂埃伯他汀A（10 μmol/L）和细胞内自由基清除剂N-乙酰半胱氨酸（400 μmol/L）部分抑制，并被c-Src酪氨酸激酶抑制剂雷迪西醇（10 μmol/L）、蛋白激酶C（PKC）抑制剂Ro31-8220（0.1 μmol/L）和丝裂原活化蛋白激酶（MAPK）激酶抑制剂PD098059（10 μmol/L）完全抑制。
我们的结果表明，UII与moxLDL协同作用，通过c-Src/PKC/MAPK途径诱导VSMC增殖，这可能解释了高血压和高胆固醇血症患者动脉粥样硬化进展相对较快的原因。
