Yang B C, Phillips M I, Mohuczy D, Meng H, Shen L, Mehta P, Mehta J L
Department of Medicine, University of Florida, College of Medicine, and the VA Medical Center, Gainesville 32610, USA.
Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1433-9. doi: 10.1161/01.atv.18.9.1433.
Angiotensin II (Ang II) promotes vascular smooth muscle growth and may be involved in the initiation and progression of atherosclerosis. To examine whether Ang II receptor expression in vascular tissues is altered in atherosclerosis, male New Zealand White rabbits were fed a high-cholesterol diet (1% cholesterol + 4% coconut oil mixed with regular chow; hypercholesterolemic group, n=12) or regular chow (control group, n=8) for 10 weeks. At the end of this period, the serum cholesterol level in the rabbits fed the high-cholesterol diet was higher than that in the control group (3616 +/- 144 versus 30 +/- 1 mg/dL, P<0.001). There was no atherosclerosis in the aortas of the control group, whereas 51 +/- 6% of the aorta was covered with atherosclerosis in the hypercholesterolemic group. Total Ang II receptor expression in the atherosclerotic aortic tissues was increased 5-fold in the hypercholesterolemic rabbits (292 +/- 28 versus 51 +/- 32 fmol/mg tissue, mean +/- SE, P<0.001), and the increased Ang II receptor expression was entirely due to enhanced Ang II type 1 (AT1) receptor expression (289 +/- 38 versus 38 +/- 18 fmol/mg, P<0.001), as Ang II type 2 receptor expression was unaltered (7 +/- 5 versus 3 +/- 2 fmol/mg, P=NS). AT1 receptors were localized primarily in the media and to some extent in the intima of the atherosclerotic aorta, as determined by immunohistochemistry with specific monoclonal and polyclonal AT1 receptor antibodies. Increased synthesis of AT1 receptor mRNA in atherosclerotic tissues was confirmed by reverse transcription-polymerase chain reaction. To evaluate the functional significance of increased AT1 receptor expression, the constrictor response of aortic rings to Ang II was examined and found to be markedly enhanced in atherosclerotic aortic rings (P<0.01 versus control aortic rings). The endothelium-dependent relaxation of aortic rings from hypercholesterolemic rabbits was markedly attenuated (P<0.001). This study shows that hypercholesterolemia in rabbits results in atherosclerosis, loss of endothelium-dependent relaxation, and increased Ang II receptor (entirely AT1 receptor) expression in aortic tissues, which may result in altered vasoreactivity.
血管紧张素II（Ang II）可促进血管平滑肌生长，并可能参与动脉粥样硬化的发生和发展。为了研究动脉粥样硬化时血管组织中Ang II受体表达是否发生改变，将雄性新西兰白兔分为两组，一组喂食高胆固醇饮食（1%胆固醇+4%椰子油与常规饲料混合；高胆固醇血症组，n=12），另一组喂食常规饲料（对照组，n=8），持续10周。在此期间结束时，喂食高胆固醇饮食的兔子血清胆固醇水平高于对照组（3616±144对30±1mg/dL，P<0.001）。对照组主动脉未出现动脉粥样硬化，而高胆固醇血症组主动脉有51±6%被动脉粥样硬化覆盖。高胆固醇血症兔子动脉粥样硬化主动脉组织中Ang II受体总表达增加了5倍（292±28对51±32fmol/mg组织，平均值±标准误，P<0.001），且Ang II受体表达增加完全是由于1型Ang II（AT1）受体表达增强（289±38对38±18fmol/mg，P<0.001），因为2型Ang II受体表达未改变（7±5对3±2fmol/mg，P=无显著性差异）。通过用特异性单克隆和多克隆AT1受体抗体进行免疫组织化学测定，发现AT1受体主要定位于动脉粥样硬化主动脉的中膜，在一定程度上也定位于内膜。通过逆转录-聚合酶链反应证实动脉粥样硬化组织中AT1受体mRNA合成增加。为了评估AT1受体表达增加的功能意义，检测了主动脉环对Ang II的收缩反应，发现动脉粥样硬化主动脉环的收缩反应明显增强（与对照主动脉环相比，P<0.01）。高胆固醇血症兔子主动脉环的内皮依赖性舒张明显减弱（P<0.001）。本研究表明，兔子的高胆固醇血症会导致动脉粥样硬化、内皮依赖性舒张功能丧失以及主动脉组织中Ang II受体（完全是AT1受体）表达增加，这可能导致血管反应性改变。
