Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice
Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice
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DOI：
10.1152/ajpheart.00862.2005
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发表时间：
2006-08-01
影响因子：
4.8
通讯作者：
Christensen, Geir
中科院分区：
文献类型：
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作者：
Larsen, Karl-Otto;Sjaastad, Ivar;Christensen, Geir
慢性阻塞性肺疾病（COPD）可能导致肺动脉高压（PH）和右心室（RV）功能下降。然而，COPD 患者也可能出现左心室 (LV) 舒张功能障碍。我们假设肺泡缺氧会引起左心室舒张功能障碍以及舒张期期间控制 Ca2+ 从细胞质中去除的蛋白质的变化。将暴露于 10% 氧气 1、2 或 4 周的小鼠与对照组进行比较。在全身麻醉下用多普勒超声心动图和微换能器导管评估心脏血流动力学。缺氧4周后，与对照组相比，肺动脉血流加速时间更短，右心室压力更高（均P < 0.05）。在右心室和左心室中，与对照相比，4周的缺氧导致等容压衰减时间常数延长（51%右心室，43%左心室），并且最大压力下降速率降低（42%右心室，42%左心室，所有P<0.05），表明舒张功能受损和舒张功能障碍。缺氧1、2和4周后，肺泡缺氧导致右心室中Ser16磷酸化受磷蛋白（PLB）分别减少38%、47%和27%，同时，左心室中Ser16磷酸化PLB下调32%、34%和25%（均P < 0.05）。 PLB 和肌（内）质网 Ca2+ ATP 酶（SERCA2a）的量没有变化。总之，慢性肺泡缺氧会诱导 PLB Ser16 磷酸化，这可能是右心室和左心室松弛受损和舒张功能障碍的机制。
Chronic obstructive pulmonary disease (COPD) may lead to pulmonary hypertension (PH) and reduced function of the right ventricle ( RV). However, COPD patients may also develop left ventricular (LV) diastolic dysfunction. We hypothesized that alveolar hypoxia induces LV diastolic dysfunction and changes in proteins governing Ca2+ removal from cytosol during diastole. Mice exposed to 10% oxygen for 1, 2, or 4 wk were compared with controls. Cardiac hemodynamics were assessed with Doppler echocardiography and a microtransducer catheter under general anesthesia. The pulmonary artery blood flow acceleration time was shorter and RV pressure was higher after 4 wk of hypoxia compared with controls (both P < 0.05). In the RV and LV, 4 wk of hypoxia induced a prolongation of the time constant of isovolumic pressure decay (51% RV, 43% LV) and a reduction in the maximum rate of decline in pressure compared with control (42% RV, 42% LV, all P < 0.05), indicating impaired relaxation and diastolic dysfunction. Alveolar hypoxia induced a 38%, 47%, and 27% reduction in Ser16-phosphorylated phospholamban (PLB) in the RV after 1, 2, and 4 wk of hypoxia, respectively, and at the same time points, Ser16-phosphorylated PLB in the LV was downregulated by 32%, 34%, and 25% (all P < 0.05). The amounts of PLB and sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) were not changed. In conclusion, chronic alveolar hypoxia induces hypophosphorylation of PLB at Ser16, which might be a mechanism for impaired relaxation and diastolic dysfunction in both the RV and LV.