Expression of CYR61, an angiogenic immediate early gene, in arteriosclerosis and its regulation by angiotensin II

被引:93
作者
Hilfiker, A
Hilfiker-Kleiner, D
Fuchs, M
Kaminski, K
Lichtenberg, A
Rothkötter, HJ
Schieffer, B
Drexler, H
机构
[1] Hannover Med Sch, Dept Cardiol & Angiol, D-30625 Hannover, Germany
[2] Hannover Med Sch, Dept Cardiovasc Surg, D-30625 Hannover, Germany
[3] Hannover Med Sch, Ctr Anat, D-30625 Hannover, Germany
关键词
angiotensin; arteriosclerosis; arteries; genes; stenosis;
D O I
10.1161/01.CIR.0000021426.87274.62
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-The renin-angiotensin system is thought to be involved in development and progression of arteriosclerosis, thereby contributing to adverse cardiovascular events. To elucidate the role of angiotensin 11 (Ang 11) at a cellular level, we analyzed the Ang II-induced gene expression profile. Methods and Results-Genes induced on Ang 11 stimulation (10(-7) mol/L, 45 minutes) in rat smooth muscle cells were analyzed by polymerase chain reaction selected subtraction. In addition to known genes, such as interleukin 6, leukemia inhibitory factor, and c-fos, we identified CYR61, an angiogenic immediate early gene. Northern blot analysis revealed a rapid 2.5-fold increase of CYR61 transcript levels by Ang 11, peaking at 30 minutes, which was blunted by Ang 11 type I receptor blockade. Exposure of rat aortic rings to Ang 11 (30 minutes) revealed a 2-fold, and intraperitoneal injection of Ang 11 (30 minutes) in mice a 3-fold, increase of aortic CYR61 transcripts. In arteriosclerotic aortas of apolipoprotein E-deficient mice, CYR61 transcripts confirmed by in situ hybridization and proteins shown by immunohistochemistry were elevated, whereas they were hardly detectable in wild types. In human carotid atherectomies and arteriosclerotic coronary arteries, immunohistochemical analysis revealed expression of CYR61 within connective tissue in neointima, adventitia, and surrounding small capillaries and blood vessels, colocalized with ACE and Ang II. Normal human arteries showed no significant staining for CYR61 Conclusions-CYR61, an angiogenic factor, is induced by Ang 11 in vascular cells and tissue. The expression of CYR61, colocalized with Ang 11 and ACE, in small vessels of human arteriosclerotic lesions is consistent with the notion that the activated renin-angiotensin system may contribute to plaque neovascularization by enhancing regulators of microvessel formation and cell proliferation.
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收藏
页码:254 / 260
页数:7
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