Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?
Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?
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DOI：
10.1155/2016/6578578
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发表时间：
2016
影响因子：
4.3
通讯作者：
Böger RH
中科院分区：
文献类型：
--
作者：
Lüneburg N;Siques P;Brito J;Arriaza K;Pena E;Klose H;Leon-Velarde F;Böger RH
慢性间歇性缺氧（CIH）和慢性缺氧（CH）与高原肺动脉高压（HAPH）有关。不对称二甲基精氨酸（ADMA），一氧化氮合酶（NOS）抑制剂，可能有助于HAPH。本研究评估了在428 Torr的低压舱中模拟CIH或CH暴露后大鼠肺中ADMA/NO通路的变化及其潜在机制。将24只成年Wistar大鼠随机分为三组：CIH 2x2（2天缺氧/2天常氧）、CH和NX（永久常氧），持续30天。所有分析均在全肺组织中进行。用LC-MS/MS分析L-精氨酸和ADMA。在两种缺氧条件下均观察到右心室肥大（p < 0.01）和内皮NOS mRNA增加（p < 0.001），但磷酸化/非磷酸化血管舒张刺激磷蛋白（VASP）比率不变。ADMA增加（p < 0.001），而二甲基精氨酸二甲氨基水解酶（DDAH）活性仅在CH下降低（p < 0.05）。虽然精氨酸酶活性增加（p < 0.001），L-精氨酸无变化，但L-精氨酸/ADMA比值显著降低（p < 0.001）。此外，NOX 4表达仅在CH下增加（p < 0.01），但丙二醛（MDA）在CIH 2x2和CH中同样增加（高达2倍）（p < 0.001）。我们的研究结果表明，ADMA和氧化应激可能会降低NO的生物利用度，在高原缺氧，这意味着更大的肺血管反应性和张力，尽管CIH下观察到的影响更柔和。
Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH.