Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms
- Equal contributors
1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA
2 Sigfried and Janet Weis Center for Research, Geisinger Clinic, Danville, 100 North Academy Avenue, Pennsylvania 17822-2610, USA
3 Department of Pathology, Creighton University School of Medicine, Omaha, Nebraska, USA
4 Southwest National Primate Research Center, San Antonio, Texas, USA
5 Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA
6 Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA
7 Department of Pathology, Louisiana Health Sciences Center, New Orleans, Louisiana, USA
8 Office of Wayne County Medical Examiner, Detroit, Michigan, USA
9 Department of Vascular and Endovascular Surgery, Geisinger Clinic, Danville, Pennsylvania, USA
10 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
BMC Physiology 2011, 11:9 doi:10.1186/1472-6793-11-9Published: 31 May 2011
The infrarenal abdominal aorta exhibits increased disease susceptibility relative to other aortic regions. Allograft studies exchanging thoracic and abdominal segments showed that regional susceptibility is maintained regardless of location, suggesting substantial roles for embryological origin, tissue composition and site-specific gene expression.
We analyzed gene expression with microarrays in baboon aortas, and found that members of the HOX gene family exhibited spatial expression differences. HOXA4 was chosen for further study, since it had decreased expression in the abdominal compared to the thoracic aorta. Western blot analysis from 24 human aortas demonstrated significantly higher HOXA4 protein levels in thoracic compared to abdominal tissues (P < 0.001). Immunohistochemical staining for HOXA4 showed nuclear and perinuclear staining in endothelial and smooth muscle cells in aorta. The HOXA4 transcript levels were significantly decreased in human abdominal aortic aneurysms (AAAs) compared to age-matched non-aneurysmal controls (P < 0.00004). Cultured human aortic endothelial and smooth muscle cells stimulated with INF-γ (an important inflammatory cytokine in AAA pathogenesis) showed decreased levels of HOXA4 protein (P < 0.0007).
Our results demonstrated spatial variation in expression of HOXA4 in human aortas that persisted into adulthood and that downregulation of HOXA4 expression was associated with AAAs, an important aortic disease of the ageing population.