Regional Disruptions in Endothelial Nitric Oxide Pathway Associated With Bicuspid Aortic Valve

Abstract

Background. Endothelial nitric oxide (NO) synthase (eNOS) has been implicated in the development of bicuspid aortic valve (BAV) and with differential expression in the ascending aorta of BAV patients. However, little is known about functional disruptions in the eNOS pathway and the effect on BAV-associated aortic dilatation. We tested the hypothesis that eNOS function is regionally diminished in ascending thoracic aortic aneurysms associated with BAV. Methods. Thoracic aortic aneurysms specimens were collected from patients with BAV (n [ 21) or tricuspid aortic valve (n [ 12). Tissue samples were harvested from three circumferential regions corresponding to locations above the right, left, and noncoronary sinuses. Adventitial-stripped specimens containing media and intima only were analyzed for NO synthase 3 gene expression and total eNOS protein. Indicators of eNOS activity (pSer1177-eNOS) and NO bioavailability (phosphorylation of vasodilator-stimulated phosphoprotein at Ser239) were also measured. Results. NO synthase 3 and eNOS protein were elevated in the right aortic region of BAV specimens compared with tricuspid aortic valve specimens. Activation of eNOS, as indicated by pSer1177-eNOS, was higher in BAV specimens across all regions. Despite increases in eNOS and pSer1177-eNOS, BAV specimens displayed no change in pSer239-vasodilator-stimulated phosphoprotein compared with tricuspid aortic valve specimens. Conclusions. BAV is associated with regional disruptions in the eNOS pathway, most markedly in the right aortic region. The discrepancy between increased eNOS activity and the absence of increased NO bioavailability in this region provides insight into physiologic mechanisms potentially underlying the asymmetric dilatation pattern observed in BAV.

Bicuspid Aortic Valve Morphotype Correlates With Regional Antioxidant Gene Expression Profiles in the Proximal Ascending Aorta

“…Our findings of altered Sod transcription are in agreement with a recent report from our group that revealed elevated nitric oxide (NO) synthase 3 expression at the transcript and protein levels despite unchanged levels of phosphorylation of vasodilator-stimulated phosphoprotein, a downstream target of NO signaling [17], suggesting that elevated endothelial NO synthase produces superoxide and thus interferes with NO signaling in the BAV aorta. Elevated Sod1 expression in the non-aneurysmal BAV aorta might be an early combative measure against elevated superoxide generation, whereas downregulation of Sod2 and Sod3 in dilated specimens is a consequence, contributing to an overall vulnerability to oxidative stress later in the disease process.…”

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

“…44 Work from our laboratory has revealed increased eNOS expression in aortic intima-media specimens isolated from patients with BAV. 42 Despite this finding, nitric oxide bioavailability was not found to be concordantly elevated. Since uncoupling of eNOS has been associated with a lack of NO bioavailability and O 2 •− generation in the aorta, 42 we surmise that eNOS is a likely source of O 2 •− production in the BAV aorta.…”

“…41 More recently, we identified endothelial nitric oxide synthase (eNOS) as one probable source of O 2 •− in the ascending aorta. 42 Although eNOS has been implicated previously in the pathophysiology of BAV-associated aortopathy, 42–44 involvement in development or progression of the associated aortopathy is mechanistically unclear. Regional down-regulation of eNOS expression has been reported in BAV aortic specimens, 43 and single-nucleotide polymorphisms have been identified in patients with aneurysmal BAV.…”

Pathogenesis of Abdominal Aortic Aneurysm

“…In comparison to the oxidative stress in AAA, the respiratory burst occurs within the contents of a phagolysosome, so the host cell contents are protected from the ROS that are generated. Since phagocytic cells such as macrophages are also strongly implicated in the inflammatory response associated with pathology of the aortic vessel wall, it follows that membrane-bound NADPH oxidase has been suggested as one of the predominant sources of vascular ROS linked to oxidative stress in aortic pathologies such as AAA and AD [18][19][20]. .…”