- 作者：Judith C. Sluimer ; Jean-Marie Gasc ; Job L. van Wanroij ; Natasja Kisters ; Mathijs Groeneweg ; Maarten D. Sollewijn Gelpke ; Jack P. Cleutjens ; Luc H. van den Akker ; Pierre Corvol ; Bradly G. Wouters ; Mat J. Daemen ; Ann-Pascale J. Bijnens
- 刊名：Journal of the American College of Cardiology
- 出版年：2008
- 出版时间：1 April 2008
- 年：2008
- 卷：51
- 期：13
- 页码：1258-1265
- 全文大小：1452 K
Objectives
We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis.Background
Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of HIF.
Methods
To examine the presence of hypoxia in atherosclerotic plaques, the hypoxia marker pimonidazole was infused before carotid endarterectomy in 7 symptomatic patients. Also, the messenger ribonucleic acid (mRNA) and protein expression of HIF1α, HIF2α, HIF-responsive genes (vascular endothelial growth factor [VEGF], glucose transporter [GLUT]1, GLUT3, hexokinase [HK]1, and HK2), and microvessel density were determined in a larger series of nondiseased and atherosclerotic carotid arteries with microarray, quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry.
Results
Pimonidazole immunohistochemistry demonstrated the presence of hypoxia, especially within the macrophage-rich center of the lesions. Hypoxia correlated with the presence of a thrombus, angiogenesis, and expression of CD68, HIF, and VEGF. The mRNA and protein expression of HIF, its target genes, and microvessel density increased from early to stable lesions, but no changes were observed between stable and ruptured lesions.
Conclusion
This is the first study directly demonstrating hypoxia in advanced human atherosclerosis and its correlation with the presence of macrophages and the expression of HIF and VEGF. Also, the HIF pathway was associated with lesion progression and angiogenesis, suggesting its involvement in the response to hypoxia and the regulation of human intraplaque angiogenesis.