Mehta Jawahar L
Departments of Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA, mehtajl@ uams.edu.
Departments of Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
J Renin Angiotensin Aldosterone Syst. 2001 Mar;2(1_suppl):S70-S76. doi: 10.1177/14703203010020011201.
Background Several studies have shown that angiotensin II (Ang II) and oxidised low-density lipoprotein (ox-LDL) are critical factors in atherosclerosis. In this study, we examined the molecular basis of mutually facilitative interactions between Ang II and ox-LDL in human coronary artery endothelial cells (HCAECs). Methods and results We observed that incubation of cultured HCAECs with Ang II (10-12 to 10-6 M) for 24 hours caused a concentration-dependent increase in the expression of mRNA and protein of a specialised receptor for ox-LDL (LOX-1). These effects of Ang II were completely blocked by pretreatment of HCAECs with candesartan (10-6 M), a specific AT1-receptor blocker, but not by PD 123319 (10-6 M), a specific AT2-receptor blocker. On the other hand, incubation of HCAECs with ox-LDL (10 and 40 µg/ml) for 24 hours progressively upregulated AT1-, but not AT 2-, receptor mRNA and protein. Pretreatment of cells with the anti-oxidant alpha-tocopherol (1-5 x 10-6 M) inhibited the upregulation of AT1-receptor expression induced by ox-LDL (p<0.05). To determine the significance of expression of AT1-receptors and LOX-1, we measured cell injury in response to Ang II and ox-LDL. Incubation of cells with both ox-LDL and Ang II synergistically increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone (both p<0.05). Alpha-tocopherol, as well as candesartan, attenuated cell injury in response to Ang II and ox-LDL (both p<0.05). Conclusions These observations show that Ang II upregulates a novel endothelial receptor for ox-LDL (LOX-1) gene expression and ox-LDL in turn upregulates Ang II AT 1receptor gene expression. This interaction between Ang II and ox-LDL further augments cell injury in HCAECs. These findings provide basis for the use of AT1-receptor blockers and anti-oxidants in designing therapy for atherosclerosis and myocardial ischaemia.
背景 多项研究表明，血管紧张素II（Ang II）和氧化型低密度脂蛋白（ox-LDL）是动脉粥样硬化的关键因素。在本研究中，我们探讨了人冠状动脉内皮细胞（HCAECs）中Ang II与ox-LDL之间相互促进作用的分子基础。
方法与结果 我们观察到，用Ang II（10-12至10-6 M）孵育培养的HCAECs 24小时，会导致ox-LDL特异性受体（LOX-1）的mRNA和蛋白表达呈浓度依赖性增加。Ang II的这些作用被坎地沙坦（10-6 M）预处理HCAECs完全阻断，坎地沙坦是一种特异性AT1受体阻滞剂，但未被特异性AT2受体阻滞剂PD 123319（10-6 M）阻断。另一方面，用ox-LDL（10和40 μg/ml）孵育HCAECs 24小时会逐渐上调AT1受体而非AT2受体的mRNA和蛋白。用抗氧化剂α-生育酚（1-5×10-6 M）预处理细胞可抑制ox-LDL诱导的AT1受体表达上调（p<0.05）。为了确定AT1受体和LOX-1表达的意义，我们测量了细胞对Ang II和ox-LDL的损伤反应。与单独使用ox-LDL或Ang II相比，用ox-LDL和Ang II共同孵育细胞会协同增加细胞损伤，以细胞活力和乳酸脱氢酶释放来衡量（两者p<0.05）。α-生育酚以及坎地沙坦可减轻细胞对Ang II和ox-LDL的损伤反应（两者p<0.05）。
结论 这些观察结果表明，Ang II上调了一种新的ox-LDL内皮受体（LOX-1）基因表达，而ox-LDL反过来上调了Ang II AT1受体基因表达。Ang II与ox-LDL之间的这种相互作用进一步加剧了HCAECs中的细胞损伤。这些发现为在设计动脉粥样硬化和心肌缺血治疗方案时使用AT1受体阻滞剂和抗氧化剂提供了依据。
