Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase
Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase
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DOI：
10.1152/ajpheart.00392.2013
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发表时间：
2014-05-01
影响因子：
4.8
通讯作者：
Weiss, Robert M.
中科院分区：
文献类型：
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作者：
El Accaoui, Ramzi N.;Gould, Sarah T.;Weiss, Robert M.
纤维钙化主动脉瓣疾病 (FCAVD) 的危险因素与内皮源性一氧化氮 (EDNO) 生物利用度的系统性降低有关。在患有二叶式主动脉瓣（BAV）的患者中，内皮型一氧化氮合酶（eNOS）的血管表达降低，并且eNOS（-/-）小鼠的BAV患病率增加。本研究的目的是检验以下假设：EDNO 在体外减弱瓣膜间质细胞 (VIC) 的促纤维化作用，以及 EDNO 缺乏在体内加速 FAVD 的发展。研究结果表明，VIC 与主动脉瓣内皮细胞 (vlvEC) 共培养显着降低了 VIC 激活，这是 FCAVD 的关键早期阶段。 N-G-硝基-L-精氨酸甲酯或吲哚美辛可减弱 vlvECs 对 VIC 激活的抑制作用。与 vlvEC 共培养减弱了基质金属蛋白酶 9 的 VIC 表达，这取决于培养基质的硬度。与胶原蛋白 1 相比，与 vlvEC 共培养优先抑制胶原蛋白 3 的基因表达。 BAV 发生在 30% 的 eNOS(-/-) 小鼠中。 6 个月时，与野生型瓣膜相比，二尖瓣和三叶 eNOS(-/-) 主动脉瓣膜中的胶原蛋白均增加。 18个月时，eNOS(-/-)和野生型小鼠中的总胶原蛋白相似，但eNOS(-/-)小鼠中的胶原蛋白3优先增加。 6 个月和 18 个月的 eNOS(-/-) 小鼠 BAV 中钙化和细胞凋亡显着增加。值得注意的是，这些组织学变化并不伴有生理上显着的瓣膜狭窄或反流。总之，与 vlvEC 共培养可抑制特定的促纤维化 VIC 过程。在体内，eNOS 缺陷会在三叶和 BAV 中产生纤维化，但仅在 BAV 中产生钙化。
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.