Department of Pharmacology and Therapeutics, Manitoba Institute of Child Health, Winnepeg, Manitoba, Canada.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1415-24. doi: 10.1152/ajpheart.00247.2011. Epub 2011 Aug 12.
Persistent pulmonary hypertension of the newborn (PPHN) results in right ventricular (RV) hypertrophy followed by right heart failure and an associated mitochondrial dysfunction. The phospholipid cardiolipin plays a key role in maintaining mitochondrial respiratory and cardiac function via modulation of the activities of enzymes involved in oxidative phosphorylation. In this study, changes in cardiolipin and cardiolipin metabolism were investigated during the development of right heart failure. Newborn piglets (<24 h old) were exposed to a hypoxic (10% O(2)) environment for 3 days, resulting in the induction of PPHN. Two sets of control piglets were used: 1) newborn or 2) exposed to a normoxic (21% O(2)) environment for 3 days. Cardiolipin biosynthetic and remodeling enzymes, mitochondrial complex II + III activity, incorporation of [1-(14)C]linoleoyl-CoA into cardiolipin precursors, and the tetralinoleoyl-cardiolipin pool size were determined in both the RV and left ventricle (LV). PPHN resulted in an increased heart-to-body weight ratio, RV-to-LV plus septum weight ratio, and expression of brain naturetic peptide in RV. In addition, PPHN reduced cardiolipin biosynthesis and remodeling in the RV and LV, which resulted in decreased tetralinoleoyl-cardiolipin levels and reduced complex II + III activity and protein levels of mitochondrial complexes II, III, and IV in the RV. This is the first study to examine the pattern of cardiolipin metabolism during the early development of both the RV and LV of the newborn piglet and to demonstrate that PPHN-induced alterations in cardiolipin biosynthetic and remodeling enzymes contribute to reduced tetralinoleoyl-cardiolipin and mitochondrial respiratory chain function during the development of RV hypertrophy. These defects in cardiolipin may play an important role in the rapid development of RV dysfunction and right heart failure in PPHN.
新生儿持续性肺动脉高压（PPHN）导致右心室（RV）肥厚，继而导致右心衰竭和相关的线粒体功能障碍。磷脂心磷脂通过调节参与氧化磷酸化的酶的活性，在心功能和心肌功能中发挥关键作用。在这项研究中，研究了右心衰竭发展过程中心磷脂和心磷脂代谢的变化。新生仔猪（<24 小时龄）暴露于低氧（10% O(2))环境中 3 天，导致 PPHN 的发生。使用两组对照仔猪：1) 新生仔猪或 2) 暴露于常氧（21% O(2))环境中 3 天。测定 RV 和左心室（LV）中的心磷脂生物合成和重塑酶、线粒体复合物 II+III 活性、[1-(14)C]亚油酰辅酶 A 在心磷脂前体中的掺入以及四油酰心磷脂库大小。PPHN 导致心脏与体重比、RV 与 LV+室间隔重量比以及 RV 中脑利钠肽表达增加。此外，PPHN 减少了 RV 和 LV 中的心磷脂生物合成和重塑，导致四油酰心磷脂水平降低，以及 RV 中复合物 II+III 活性和线粒体复合物 II、III 和 IV 的蛋白水平降低。这是第一项研究，研究了新生仔猪 RV 和 LV 早期发育中心磷脂代谢的模式，并证明 PPHN 诱导的心磷脂生物合成和重塑酶的改变导致 RV 肥厚发育过程中心磷脂代谢的四油酰心磷脂和线粒体呼吸链功能降低。心磷脂的这些缺陷可能在 PPHN 中 RV 功能障碍和右心衰竭的快速发展中发挥重要作用。
