Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Pediatr Res. 2012 Jan;71(1):25-31. doi: 10.1038/pr.2011.10.
Chronic hypoxia increases the expression of inducible nitric oxide synthase (iNOS) mRNA and protein levels in fetal guinea pig heart ventricles. Excessive generation of nitric oxide (NO) can induce nitrosative stress leading to the formation of peroxynitrite, which can upregulate the expression of matrix metalloproteinases (MMPs). This study tested the hypothesis that maternal hypoxia increases fetal cardiac MMP9 and collagen through peroxynitrite generation in fetal hearts.
In heart ventricles, levels of malondialdehyde, 3-nitrotyrosine (3-NT), MMP9, and collagen were increased in hypoxic (HPX) vs. normoxic (NMX) fetal guinea pigs.
Thus, maternal hypoxia induces oxidative-nitrosative stress and alters protein expression of the extracellular matrix (ECM) through upregulation of the iNOS pathway in fetal heart ventricles. This identifies iNOS-derived NO as an important stimulus for initiating the adverse effects of peroxynitrite in HPX fetal hearts.
Pregnant guinea pigs were exposed to normoxia (room air) or hypoxia (10.5% O(2), 14 d) before term (term ≈ 65 d) and administered water, L-N6-(1-iminoethyl)-lysine (LNIL), an iNOS inhibitor, or N-acetylcysteine (NAC), an antioxidant.
慢性缺氧会增加胎鼠心室中诱导型一氧化氮合酶（iNOS）mRNA 和蛋白水平的表达。过量生成的一氧化氮（NO）可诱导硝化应激，导致过氧亚硝酸盐的形成，从而上调基质金属蛋白酶（MMPs）的表达。本研究通过检测胎鼠心脏中过氧亚硝酸盐的生成，验证了母体缺氧会增加胎儿心脏 MMP9 和胶原的假说。
在胎鼠心室中，与常氧（NMX）组相比，缺氧（HPX）组胎鼠心脏中的丙二醛、3-硝基酪氨酸（3-NT）、MMP9 和胶原的水平增加。
因此，母体缺氧通过诱导胎儿心脏中 iNOS 通路的上调，诱导氧化-硝化应激，并改变细胞外基质（ECM）的蛋白表达。这表明 iNOS 衍生的 NO 是启动 HPX 胎儿心脏中过氧亚硝酸盐不良作用的重要刺激因素。
在足月（约 65 天）前，将怀孕的豚鼠暴露于常氧（室内空气）或缺氧（10.5% O2，14 天）环境中，并给予水、iNOS 抑制剂 L-N6-（1-亚氨基乙基）-赖氨酸（LNIL）或抗氧化剂 N-乙酰半胱氨酸（NAC）。
