Increased Expression of Lamin A/C Correlate with Regions of High Wall Stress in Abdominal Aortic Aneurysms

Abstract

Background: Since aortic diameter is the most significant risk factor for rupture, we sought to identify stress-dependent changes in gene expression to illuminate novel molecular processes in aneurysm rupture. Materials and Methods: We constructed finite element maps of abdominal computerized tomography scans (CTs) of seven abdominal aortic aneurysm (AAA) patients to map wall stress. Paired biopsies from high-and low-stress areas were collected at surgery using vascular landmarks as coordinates. Differential gene expression was evaluated by Illumina Array analysis, using the whole genome DNA-mediated, annealing, selection, extension, and ligation (DASL) gene chip (n = 3 paired samples). Conclusion:Lamin A/C protein is specifically increased in areas of high wall stress in AAA from patients, but is not increased on other vascular beds of aneurysm patients, suggesting that its elevation may be a compensatory response to the pathobiology leading to aneurysms.

Neutrophil Elastase-Derived Fibrin Degradation Products Indicate Presence of Abdominal Aortic Aneurysms and Correlate with Intraluminal Thrombus Volume

“…An intriguing concept of biomechanical-biological interactions in AAA was that of segmental aortic stiffening increasing the axial tensile stress in adjacent, compliant, segments causing increased inflammation and proteolysis, which also correlated with age-related changes in the human aorta (281). Investigations into associations between gene expression and wall stress or the estimated ratio between wall stress and wall strength have pointed to differences in expression of lamin A/C and genes related to ECM and cytokine signaling, while strong associations surviving correction for multiple testing are difficult to obtain (228,229,282). On the protein/structural/cellular level, high ratio between wall stress and wall strength was associated with decreased vSMCs and elastic fibers as well as more cholesterol and calcified plaques, whereas increased wall stress was associated with increased collagen 1, III and total collagen (283).…”

“…The RNA from a blood sample of a patient with AAA differs significantly from that of healthy controls, with increased expression of genes related to apoptosis, immunity and proteolysis, but also differs from blood taken from patients with carotid artery stenosis (225,226). One study examined the association between global gene expression and a signal on positron emission tomography (PET) CT, whereas others have compared regions of high and low biomechanical wall stress or rupture risk (227)(228)(229).…”

Role of vascular remodeling in atherosclerosis and aortic aneurysm

“…159 Increased expression of lamin A was observed in the region of high wall-stress and not in the non-aneurysmal vascular beds of AAA patients. 160 Furthermore, physiological pulsatile stretch of VSMC in vitro caused a time-dependent elevation of prelamin A and lamin A expression. 160 Lamin A is also a direct activator of Sirtuin 1 (SIRT1).…”

“…160 Furthermore, physiological pulsatile stretch of VSMC in vitro caused a time-dependent elevation of prelamin A and lamin A expression. 160 Lamin A is also a direct activator of Sirtuin 1 (SIRT1). 161 SIRT1 is a nicotinamide adenine dinucleotide-dependent protein deacetylase, highly expressed in the vasculature.…”