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Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase.

American journal of physiology. Heart and circulatory physiology (2014-03-13)
Ramzi N El Accaoui, Sarah T Gould, Georges P Hajj, Yi Chu, Melissa K Davis, Diane C Kraft, Donald D Lund, Robert M Brooks, Hardik Doshi, Kathy A Zimmerman, William Kutschke, Kristi S Anseth, Donald D Heistad, Robert M Weiss

Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS(-/-) mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo. As a result of the study, coculture of VICs with aortic valve endothelial cells (vlvECs) significantly decreased VIC activation, a critical early phase of FCAVD. Inhibition of VIC activation by vlvECs was attenuated by N(G)-nitro-l-arginine methyl ester or indomethacin. Coculture with vlvECs attenuated VIC expression of matrix metalloproteinase-9, which depended on stiffness of the culture matrix. Coculture with vlvECs preferentially inhibited collagen-3, compared with collagen-1, gene expression. BAV occurred in 30% of eNOS(-/-) mice. At age 6 mo, collagen was increased in both bicuspid and trileaflet eNOS(-/-) aortic valves, compared with wild-type valves. At 18 mo, total collagen was similar in eNOS(-/-) and wild-type mice, but collagen-3 was preferentially increased in eNOS(-/-) mice. Calcification and apoptosis were significantly increased in BAV of eNOS(-/-) mice at ages 6 and 18 mo. Remarkably, these histological changes were not accompanied by physiologically significant valve stenosis or regurgitation. In conclusion, coculture with vlvECs inhibits specific profibrotic VIC processes. In vivo, eNOS deficiency produces fibrosis in both trileaflet and BAVs but produces calcification only in BAVs.

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Formaldehyde solution, stabilized with methanol, ~37 wt. % in H2O, certified reference material
Formaldehyde solution, ACS reagent, 37 wt. % in H2O, contains 10-15% Methanol as stabilizer (to prevent polymerization)
Formaldehyde-12C solution, 20% in H2O, 99.9 atom % 12C
2-Phenylindole, technical grade, 95%
Formaldehyde solution, tested according to Ph. Eur.
Formaldehyde solution, meets analytical specification of USP, ≥34.5 wt. %
Formaldehyde solution, for molecular biology, BioReagent, ≥36.0% in H2O (T)
Formaldehyde solution, for molecular biology, 36.5-38% in H2O
Formaldehyde solution, meets analytical specification of Ph. Eur., BP, 35 wt. %, contains 10% methanol as stabilizer
Formaldehyde solution, contains 10-15% methanol as stabilizer, 37 wt. % in H2O