Kamide K, Hori M T, Zhu J H, Barrett J D, Eggena P, Tuck M L
From the Division of Endocrinology and Vascular Biopharmacology/Renin Biochemistry Laboratories, Department of Veterans Affairs Medical Center, Sepulveda, CA 91343, USA.
Hypertension. 1998 Sep;32(3):482-7. doi: 10.1161/01.hyp.32.3.482.
Insulin has been shown to directly affect blood vessel tone and to promote vascular hypertrophy, but the mechanism of these actions remains uncertain. Because angiotensin I (Ang I)-converting enzyme inhibitors have been shown to improve insulin action and to impede the progression of vascular hypertrophy in hypertensive animal models, it is possible that the vascular properties of insulin may be mediated through the tissue renin-angiotensin system (RAS). To evaluate this relationship, we first investigated the effect of insulin on components of the RAS using cultured rat vascular smooth muscle cells (VSMCs). Insulin treatment (1000 microU/mL) markedly increased angiotensinogen mRNA expression and angiotensinogen production. We next investigated the role of the RAS in insulin-mediated cell proliferation, using [3H]thymidine uptake. Studies were done both with insulin alone and in the presence of captopril (1x10(-7) to 10(-5) mol/L) and losartan (1x10(-9) to 10(-7) mol/L). [3H]Thymidine uptake was increased significantly by 1000 microU/mL insulin, and this stimulation was reduced by 1x10(-6) mol/L captopril (-38.8%, P<0.05) and by 1x10(-8) mol/L losartan (-37. 5%, P<0.05). Further studies showed that the degree of insulin-mediated [3H]thymidine uptake in VSMCs could be duplicated by 4x10(-10) mol/L Ang II. Losartan reduced the effects of both Ang II and insulin on [3H]thymidine uptake by about 40% to 45% of baseline (P<0.05). Captopril reduced insulin-mediated [3H]thymidine uptake but did not affect Ang II-mediated [3H]thymidine uptake. In summary, insulin induced significant stimulation of angiotensinogen expression and production and stimulated growth similar to that seen with Ang II in cultured rat VSMCs. Inhibition of Ang II production or its binding to the Ang II type 1 (AT1) receptor inhibited insulin-mediated growth in a fashion similar to that seen with inhibition of Ang II-mediated growth. Thus, insulin can modulate the vascular RAS, and the effect of insulin on vascular growth may be via direct effects on angiotensinogen expression and translation operative through both the AT1 receptor and the conversion of Ang I to Ang II.
胰岛素已被证明可直接影响血管张力并促进血管肥大，但其作用机制仍不确定。由于血管紧张素I（Ang I）转换酶抑制剂已被证明可改善胰岛素作用并阻止高血压动物模型中血管肥大的进展，因此胰岛素的血管特性可能是通过组织肾素-血管紧张素系统（RAS）介导的。为了评估这种关系，我们首先使用培养的大鼠血管平滑肌细胞（VSMC）研究了胰岛素对RAS各成分的影响。胰岛素处理（1000微单位/毫升）显著增加了血管紧张素原mRNA表达和血管紧张素原的产生。接下来，我们使用[3H]胸腺嘧啶核苷摄取法研究了RAS在胰岛素介导的细胞增殖中的作用。研究分别在单独使用胰岛素以及存在卡托普利（1×10⁻⁷至10⁻⁵摩尔/升）和氯沙坦（1×10⁻⁹至10⁻⁷摩尔/升）的情况下进行。1000微单位/毫升胰岛素显著增加了[3H]胸腺嘧啶核苷摄取，而1×10⁻⁶摩尔/升卡托普利（-38.8%，P<0.05）和1×10⁻⁸摩尔/升氯沙坦（-37.5%，P<0.05）可降低这种刺激作用。进一步的研究表明，4×10⁻¹⁰摩尔/升的Ang II可模拟VSMC中胰岛素介导的[3H]胸腺嘧啶核苷摄取程度。氯沙坦将Ang II和胰岛素对[3H]胸腺嘧啶核苷摄取的影响降低至基线的约40%至45%（P<0.05）。卡托普利降低了胰岛素介导的[3H]胸腺嘧啶核苷摄取，但不影响Ang II介导的[3H]胸腺嘧啶核苷摄取。总之，胰岛素在培养的大鼠VSMC中诱导了血管紧张素原表达和产生的显著刺激，并刺激了与Ang II相似的生长。抑制Ang II的产生或其与血管紧张素II 1型（AT1）受体的结合以类似于抑制Ang II介导的生长的方式抑制了胰岛素介导的生长。因此，胰岛素可调节血管RAS，胰岛素对血管生长的影响可能是通过对血管紧张素原表达和翻译的直接作用，通过AT1受体以及Ang I向Ang II的转化来实现的。
