Regional Disruptions in Endothelial Nitric Oxide Pathway Associated With Bicuspid Aortic Valve.
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.
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Mary P
MP
Kotlarczyk
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Marie
M
Billaud
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Benjamin R
BR
Green
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Jennifer C
JC
Hill
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Sruti
S
Shiva
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Eric E
EE
Kelley
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania.
Julie A
JA
Phillippi
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: gleasontg@upmc.edu.
Thomas G
TG
Gleason
D000368:Aged; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000601:surgery; D001021:Aortic Valve / Q000002:abnormalities* / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D015815:Cell Adhesion Molecules / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006349:Heart Valve Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D011446:Prospective Studies; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics*; D020858:Tissue and Organ Harvesting; D014261:Tricuspid Valve / Q000502:physiology; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D052250:Nitric Oxide Synthase Type III