Greene E L, Lu G, Zhang D, Egan B M
Department of Internal Medicine, Medical University of South Carolina, Charleston, USA.
Hypertension. 2001 Feb;37(2):308-12. doi: 10.1161/01.hyp.37.2.308.
Obese hypertensive patients with cardiovascular risk factor clustering and increased risk for atherosclerotic disease have increased plasma nonesterified fatty acid levels, including oleic acid (OA), and a more active renin-angiotensin-aldosterone system. Vascular smooth muscle cell (VSMC) migration and proliferation participate in the development of atherosclerotic plaque. OA and angiotensin (Ang) II induce synergistic mitogenic responses in VSMCs through sequential signaling pathways dependent on the activation of protein kinase C (PKC), oxidants (reactive oxygen species, ROS), and extracellular signal-regulated kinase (ERK) activation. We tested the hypotheses that (1) OA and Ang II have additive or synergistic effects on VSMC migration and (2) PKC, ROS, and mitogen-activated protein kinase are critical signaling molecules. OA at 100 micromol/L increases VSMC migration 60+/-10% over control (P:<0.001). Ang II (10(-)(9) mol/L) increases VSMC migration by 62+/-13% and 73% over control, respectively (P:<0.01). Coincubation of cells with OA and Ang II produces a nearly additive increase in VSMC cell migration at 107+/-20% (P:<0.01). Increases in VSMC migration induced by OA alone and combined with Ang II were reduced by PKC inhibition and downregulation. VSMC migration in response to OA alone and with Ang II was also inhibited by N:-acetyl-cysteine, MEK inhibition, and ERK antisense. VSMC migration in response to OA alone or combined with Ang II is dependent on activation of PKC, ROS, and ERK activation, further raising the possibility that increased plasma nonesterified fatty acids and an activated renin-angiotensin-aldosterone system in subjects with the risk factor cluster contribute to accelerated atherosclerosis through a PKC, ROS, and ERK-dependent signaling pathway.
伴有心血管危险因素聚集且动脉粥样硬化疾病风险增加的肥胖高血压患者，其血浆非酯化脂肪酸水平升高，包括油酸（OA），并且肾素-血管紧张素-醛固酮系统更为活跃。血管平滑肌细胞（VSMC）迁移和增殖参与动脉粥样硬化斑块的形成。OA和血管紧张素（Ang）II通过依赖蛋白激酶C（PKC）激活、氧化剂（活性氧，ROS）和细胞外信号调节激酶（ERK）激活的顺序信号通路，在VSMC中诱导协同促有丝分裂反应。我们检验了以下假设：（1）OA和Ang II对VSMC迁移具有相加或协同作用；（2）PKC、ROS和丝裂原活化蛋白激酶是关键信号分子。100微摩尔/升的OA使VSMC迁移比对照组增加60±10%（P<0.001）。Ang II（10⁻⁹摩尔/升）使VSMC迁移分别比对照组增加62±13%和73%（P<0.01）。细胞与OA和Ang II共同孵育使VSMC细胞迁移增加近相加效应，达到107±20%（P<0.01）。单独OA以及与Ang II联合诱导的VSMC迁移增加，通过PKC抑制和下调而降低。单独OA以及与Ang II联合作用时，N-乙酰半胱氨酸、MEK抑制和ERK反义寡核苷酸也抑制VSMC迁移。单独OA或与Ang II联合作用时，VSMC迁移依赖于PKC、ROS和ERK激活，这进一步增加了以下可能性，即具有危险因素聚集的受试者血浆非酯化脂肪酸增加和肾素-血管紧张素-醛固酮系统激活，通过PKC、ROS和ERK依赖的信号通路促成动脉粥样硬化加速发展。
