Heinis Frazer I, Andersson Kristin B, Christensen Geir, Metzger Joseph M
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America ; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2013 Nov 4;8(11):e79609. doi: 10.1371/journal.pone.0079609. eCollection 2013.
The cardiac SERCA2 Ca(2+) pump is critical for maintaining normal Ca(2+) handling in the heart. Reduced SERCA2a content and blunted Ca(2+) reuptake are frequently observed in failing hearts and evidence implicates poor cardiac Ca(2+) handling in the progression of heart failure. To gain insight into mechanism we investigated a novel genetic mouse model of inducible severe and progressive SERCA2 deficiency (inducible Serca2 knockout, SERCA2 KO). These mice eventually die from overt heart failure 7-10 weeks after knockout but as yet there have been no reports on intrinsic mechanical performance at the isolated whole heart organ level. Thus we studied whole-organ ex vivo function of hearts isolated from SERCA2 KO mice at one and four weeks post-knockout in adult animals. We found that isolated KO heart function was only modestly impaired one week post-knockout, when SERCA2a protein was 32% of normal. At four weeks post-knockout, function was severely impaired with near non-detectable levels of SERCA2. During perfusion with 10 mM caffeine, LV developed pressures were similar between 4-week KO and control hearts, and end-diastolic pressures were lower in KO. When hearts were subjected to ischemia-reperfusion injury, recovery was not different between control and KO hearts at either one or four weeks post-knockout. Our findings indicate that ex vivo function of isolated SERCA2 KO hearts is severely impaired long before symptoms appear in vivo, suggesting that physiologically relevant heart function in vivo can be sustained for weeks in the absence of robust SR Ca(2+) flux.
心脏肌浆网Ca(2+) - ATP酶（SERCA2）对维持心脏正常的Ca(2+) 处理至关重要。在衰竭心脏中，常观察到SERCA2a含量降低和Ca(2+) 再摄取减弱，且有证据表明心脏Ca(2+) 处理不良与心力衰竭的进展有关。为深入了解其机制，我们研究了一种新型的可诱导严重且进行性SERCA2缺乏的基因小鼠模型（可诱导的Serca2基因敲除，SERCA2 KO）。这些小鼠在基因敲除后7 - 10周最终死于明显的心力衰竭，但目前尚无关于分离的全心脏器官水平内在机械性能的报道。因此，我们研究了成年动物基因敲除后1周和4周从SERCA2 KO小鼠分离的心脏的全器官离体功能。我们发现，基因敲除1周后，当SERCA2a蛋白为正常水平的32%时，分离的KO心脏功能仅轻度受损。基因敲除4周后，功能严重受损，SERCA2水平几乎检测不到。在灌注10 mM咖啡因时，4周龄KO心脏和对照心脏的左心室舒张末压相似，而KO心脏的舒张末压较低。当心脏遭受缺血 - 再灌注损伤时，基因敲除后1周和4周，对照心脏和KO心脏的恢复情况没有差异。我们的研究结果表明，在体内症状出现之前很久，分离的SERCA2 KO心脏的离体功能就已严重受损，这表明在缺乏强大的肌浆网Ca(2+) 通量的情况下，体内生理相关的心脏功能可持续数周。
