Dataset Information

Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms.

ABSTRACT:

Background

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.

Results

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-? (an important inflammatory cytokine in AAA pathogenesis) showed decreased levels of HOXA4 protein (P < 0.0007).

Conclusions

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.

SUBMITTER: Lillvis JH

PROVIDER: S-EPMC3125234 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms.

Lillvis John H JH Erdman Robert R Schworer Charles M CM Golden Alicia A Derr Kimberly K Gatalica Zoran Z Cox Laura A LA Shen Jianbin J Vander Heide Richard S RS Lenk Guy M GM Hlavaty Leigh L Li Li L Elmore James R JR Franklin David P DP Gray John L JL Garvin Robert P RP Carey David J DJ Lancaster Wayne D WD Tromp Gerard G Kuivaniemi Helena H

BMC physiology 20110531

<h4>Background</h4>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.<h4>Results</h4>We analyzed gene expression with microarrays in baboon aortas, and found that members of the HOX gene family exhibi ...[more]

PMID: 21627813

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Project description:Background: Current clinical practice for the assessment of abdominal aortic aneurysms (AAA) is based on vessel diameter and does not account for the multifactorial, heterogeneous remodeling that results in the regional weakening of the aortic wall leading to aortic growth and rupture. The present study was conducted to determine correlations between a novel non-invasive surrogate measure of regional aortic weakening and the results from invasive analyses performed on corresponding ex vivo aortic samples. Tissue samples were evaluated to classify local wall weakening and the likelihood of further degeneration based on non-invasive indices. Methods: A combined, image-based fluid dynamic and in-vivo strain analysis approach was used to estimate the Regional Aortic Weakness (RAW) index and assess individual aortas of AAA patients prior to elective surgery. Nine patients were treated with complete aortic resection allowing the systematic collection of tissue samples that were used to determine regional aortic mechanics, microstructure and gene expression by means of mechanical testing, microscopy and transcriptomic analyses. Results: The RAW index was significantly higher for samples exhibiting lower mechanical strength (p = 0.035) and samples classified as low elastin content (p = 0.020). Samples with higher RAW index had the greatest number of genes differentially expressed compared to any constitutive metric. High RAW samples showed a decrease in gene expression for elastin and a down-regulation of pathways responsible for cell movement, reorganization of cytoskeleton, and angiogenesis. Conclusions: This work describes the first AAA index free of assumptions for material properties and accounting for patient-specific mechanical behavior in relation to aneurysm strength. Use of the RAW index captured biomechanical changes linked to the weakening of the aorta and revealed changes in microstructure and gene expression. This approach has the potential to provide an improved tool to aid clinical decision-making in the management of aortic pathology.

Project description:ObjectiveSignificant regional variation in surgical rates has been identified following multiple surgical procedures. However, limited data have examined the regional variability in patient selection and treatment of abdominal aortic aneurysms (AAAs). This study aimed to evaluate regional variation in patient selection, perioperative management, and operative approach for the repair of AAAs.MethodsAll patients undergoing open repair or endovascular aneurysm repair (EVAR) of an AAA in the Vascular Quality Initiative from 2009 to 2014 were identified. All regional groups were deidentified, and those with fewer than 100 open repairs were combined into a single region.ResultsWe identified 17,269 elective repairs (EVAR, 13,759; open, 3510) and 1462 ruptured AAAs (EVAR, 749; open, 713). There was significant regional variation in the use of EVAR for elective repair (range, 66%-88%; P < .01) and ruptured AAA repair (40%-80%; P < .01). The median diameter for elective repair was similar among regions (EVAR, 5.4 cm; open, 5.7 cm). There was wide variation in the treatment of small aneurysms in male patients (<5.5 cm) for EVAR (34%-49%; P < .01) and open repair (17%-38%; P < .01) and variation in the treatment of small aneurysms in female patients (<5 cm) for EVAR (14%-32%; P < .01) but not significant for open repair (6%-24%). For elective cases, preoperative aspirin (EVAR, 50%-75% [P < .01]; open, 49%-78% [P < .01]) and statin use (EVAR, 61%-75% [P < .01]; open, 56%-80% [P < .01]) varied widely. Among elective cardiac patients, preoperative management varied significantly, including beta-blocker use (EVAR, 66%-78% [P < .01]; open, 69%-88% [P = .01]) and the frequency of stress tests (EVAR, 33%-64% [P < .01]; open, 31%-73% [P < .01]). Among open repairs for aneurysms extending at or beyond the juxtarenal segment, there was wide variation in the use of retroperitoneal exposures (7%-70%; P < .01) and adjunctive renal protective measures (cold renal perfusion, 2%-43% [P < .01]; mannitol, 47%-92% [P < .01]).ConclusionsSignificant regional variation exists in patient selection, perioperative management, and operative approach for the repair of AAA. Definitive evidence is lacking in many aspects of operative care, including the use of the retroperitoneal approach and renal protective strategies. However, this variation emphasizes the importance of research to determine best practice in the areas of greatest variation. Furthermore, where current clinical process measures exist and data are clear, such as the use of statin and antiplatelet agents, the high degree of variation should serve as an impetus for regional quality improvement projects.

Dataset Information

Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms.

Background

Results

Conclusions

Publications

Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms.

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