Dysregulation of Endothelial Nitric Oxide Synthase Does Not Depend on Hemodynamic Alterations in Bicuspid Aortic Valve Aortopathy

Abstract

Background Bicuspid aortic valves (BAVs) predispose to ascending aortic aneurysm. Turbulent blood flow and genetic factors have been proposed as underlying mechanisms. Endothelial nitric oxide synthase (eNOS) has been implicated in BAV aortopathy, and its expression is regulated by wall shear stress. We hypothesized that if turbulent flow induces aneurysm formation in patients with a BAV, regional differences in eNOS expression would be observed in BAVs. Methods and Results Ascending aortic specimens were harvested intraoperatively from 48 patients with tricuspid aortic valve (19 dilated, 29 nondilated) and 38 with BAV (28 dilated, 10 nondilated) undergoing cardiac surgery. eNOS mRNA and protein concentration were analyzed at the convex and concave aortic wall. In nondilated aortas, eNOS mRNA and protein concentration were decreased in BAV compared with tricuspid aortic valve (all P <0.05). eNOS expression was increased in association with dilation in BAV aortas ( P =0.03), but not in tricuspid aortic valve aortas ( P =0.63). There were no regional differences in eNOS mRNA or protein concentration in BAV aortas (all P >0.05). However, eNOS expression was increased at the concave wall (versus convexity) in tricuspid aortic valve dilated aortas (all P <0.05). Conclusions Dysregulated eNOS occurs independent of dilation in BAV aortas, suggesting a potential role for aberrantly regulated eNOS expression in the development of BAV‐associated aneurysms. The absence of regional variations of eNOS expression suggests that eNOS dysregulation in BAV aortas is the result of underlying genetic factors associated with BAV disease, rather than changes stimulated by hemodynamic alterations. These findings provide insight into the underlying mechanisms of aortic dilation in patients with a BAV.

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

“…However, this difference was not present in the case of dilated ascending aortas, suggesting that aberrant eNOS expression in BAV aortas may precede aneurysm development. This finding would support the theory of the genetic factors rather than hemodynamic factors as the cause of BAV [ 82 ].…”

Endothelial nitric oxide synthase alterations are independent of turbulence in the aorta of patients with a unicuspid aortic valve

“…Altered eNOS signaling has been observed in BAV-associated ascending aortas. 15 , 18 , 21 , 22 , 23 Although its role is unclear, eNOS may be involved in extracellular matrix remodeling within the aortic wall. In buckled arteries, for instance, eNOS protein levels were decreased alongside increased matrix metalloproteinase 2 levels and a reduction in collagen content.…”

“…RNA isolation, reverse transcription, and quantitative real-time PCR were performed as previously described. 18 To summarize, RNA isolation was performed with the mirVana PARIS Kit (Ambion, Austin, Tex) and reverse transcription was achieved by using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, Calif) according to the manufacturers' instructions. Quantitative real-time PCR was performed on 96-well TaqMan Plates (Applied Biosystems), with TaqMan Gene Expression Assays (Applied Biosystems).…”

“…Quantification of eNOS protein levels in ascending aortic tissue was carried out as previously described. 18 To summarize, protein isolation was achieved through the Protein Quant Sample Lysis Kit (Life Technologies, Carlsbad, Calif). Protein expression of eNOS was determined by Western Blot analysis, using polyacrylamide Bis-Tris 4%-12% gels (Life Technologies).…”

Investigation on the mechanisms of guiqi huoxue capsule for treating cervical spondylosis based on network pharmacology and molecular docking

“…[ 79 ] Variations in the NOS3 are made in association with susceptibility to coronary spasm. [ 80 ] NO mediates vasodilation, and the release of NO is regulated by endothelial NOS3. [ 81 ] CSR pathogenesis is associated with inflammation and blood vessels, and these possible key targets can regulate inflammatory factors and angiogenesis.…”