Chronic hypoxia induces right heart failure in caveolin-1-/- mice
Chronic hypoxia induces right heart failure in caveolin-1-/- mice
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DOI：
10.1152/ajpheart.01140.2011
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发表时间：
2012-06-01
影响因子：
4.8
通讯作者：
Bauer, Philip M.
中科院分区：
文献类型：
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作者：
Cruz, J. Agustin;Bauer, Eileen M.;Bauer, Philip M.
克鲁兹·贾、鲍尔·EM、罗德里格斯·AI、Gangopadhyay A、Zeineh NS、王勇、希瓦·S、冠军HC、鲍尔·PM慢性低氧诱导小窝蛋白-1-/-小鼠右心衰竭。Am J Physiol心脏圈Physiol 302：H2518-H2527,2012。2012年4月13日首次出版；doi：10.1152/ajpheart.01140.2011.-Cavelin-1(CAV-1)-/-小鼠随着年龄的增长会出现轻微的肺动脉高压。在这项研究中，我们试图确定慢性低氧对年轻的Cav-1-/-小鼠的影响，这是一种已建立的肺动脉高压模型，没有可测量的肺动脉高压迹象。CAV-1-/-小鼠暴露在慢性低氧环境中，导致右室(RV)收缩压(RVSP)最初升高，与野生型(WT)小鼠相似。三周后，CAV-1-/-小鼠的RVSP下降，而WT小鼠的RVSP保持不变。与WT小鼠相比，Cav-1-/-小鼠RVSP下降伴随心输出量减少、RV肥厚增加、RV间质纤维化、RV肌浆网(Endo)钙-ATPase 2a mRNA减少和RV功能下降。重要的是，WT和Cav-1-/-小鼠在肺血管重构方面的差异很小，低氧Cav-1-/-小鼠的左心功能正常。机械上，CAV-1-/-小鼠RV内皮型一氧化氮合酶解偶联增加，蛋白激酶G酪氨酸硝化增加。在表达内皮特异性Cav-1转基因或一氧化氮合酶抑制的Cav-1-/-小鼠中，这些血流动力学、组织学和分子变化被阻止。这些数据表明，在Cav-1-/-小鼠中，内皮型一氧化氮合酶解偶联导致的氧化/亚硝化应激增加改变了右室对压力超负荷的反应，加速了右室功能的恶化。
Cruz JA, Bauer EM, Rodriguez AI, Gangopadhyay A, Zeineh NS, Wang Y, Shiva S, Champion HC, Bauer PM. Chronic hypoxia induces right heart failure in caveolin-1 -/- mice. Am J Physiol Heart Circ Physiol 302: H2518-H2527, 2012. First published April 13, 2012; doi:10.1152/ajpheart.01140.2011.-Caveolin-1 (Cav-1) -/- mice develop mild pulmonary hypertension as they age. In this study, we sought to determine the effect of chronic hypoxia, an established model of pulmonary hypertension, on young Cav-1 -/- mice with no measurable signs of pulmonary hypertension. Exposure of Cav-1 -/- mice to chronic hypoxia resulted in an initial rise in right ventricular (RV) systolic pressure (RVSP) similar to wild-type (WT) mice. By three weeks RVSP decreased in the Cav-1 -/- mice, whereas it was maintained in WT mice. The drop in RVSP in Cav-1 -/- mice was accompanied by decreased cardiac output, increased RV hypertrophy, RV interstitial fibrosis, decreased RV sarco(endo) plasmic reticulum Ca2+-ATPase 2a mRNA and decreased RV function compared with WT mice. Importantly, minimal differences were noted in pulmonary vascular remodeling between WT and Cav-1 -/- mice, and left ventricular function was normal in hypoxic Cav-1 -/- mice. Mechanistically, increased endothelial nitric oxide synthase uncoupling and increased tyrosine nitration of protein kinase G were detected in the RV of Cav-1 -/- mice. These hemodynamic, histological, and molecular changes were prevented in Cav-1 -/- mice expressing an endothelial-specific Cav-1 transgene or by nitric oxide synthase inhibition. These data suggest that, in Cav-1 -/- mice, increased oxidative/nitrosative stress due to endothelial nitric oxide synthase uncoupling modifies the response of the RV to pressure overload, accelerating the deterioration of RV function.