Hassink Rutger J, Pasumarthi Kishore B, Nakajima Hidehiro, Rubart Michael, Soonpaa Mark H, de la Rivière Aart Brutel, Doevendans Pieter A, Field Loren J
Department of Cardiology, University Medical Center, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Cardiovasc Res. 2008 Apr 1;78(1):18-25. doi: 10.1093/cvr/cvm101. Epub 2007 Dec 12.
Cardiomyocyte loss is a major contributor to the decreased cardiac function observed in diseased hearts. Previous studies have shown that cardiomyocyte-restricted cyclin D2 expression resulted in sustained cell cycle activity following myocardial injury in transgenic (MHC-cycD2) mice. Here, we investigated the effects of this cell cycle activation on cardiac function following myocardial infarction (MI).
MI was induced in transgenic and non-transgenic mice by left coronary artery occlusion. At 7, 60, and 180 days after MI, left ventricular pressure-volume measurements were recorded and histological analysis was performed. MI had a similar adverse effect on cardiac function in transgenic and non-transgenic mice at 7 days post-injury. No improvement in cardiac function was observed in non-transgenic mice at 60 and 180 days post-MI. In contrast, the transgenic animals exhibited a progressive and marked increase in cardiac function at subsequent time points. Improved cardiac function in the transgenic mice at 60 and 180 days post-MI correlated positively with the presence of newly formed myocardial tissue which was not apparent at 7 days post-MI. Intracellular calcium transient imaging indicated that cardiomyocytes present in the newly formed myocardium participated in a functional syncytium with the remote myocardium.
These findings indicate that cardiomyocyte cell cycle activation leads to improvement of cardiac function and morphology following MI and may represent an important clinical strategy to promote myocardial regeneration.
心肌细胞丢失是患病心脏中心脏功能下降的主要原因。先前的研究表明，在转基因（MHC-cycD2）小鼠中，心肌细胞特异性的细胞周期蛋白D2表达导致心肌损伤后细胞周期活动持续存在。在此，我们研究了这种细胞周期激活对心肌梗死后心脏功能的影响。
通过左冠状动脉闭塞在转基因和非转基因小鼠中诱导心肌梗死。在心肌梗死后7天、60天和180天，记录左心室压力-容积测量值并进行组织学分析。在损伤后7天，心肌梗死对转基因和非转基因小鼠的心脏功能产生类似的不利影响。在心肌梗死后60天和180天，未观察到非转基因小鼠的心脏功能有改善。相比之下，转基因动物在随后的时间点心脏功能呈现出逐渐且显著的增加。在心肌梗死后60天和180天，转基因小鼠心脏功能的改善与新形成的心肌组织的存在呈正相关，而在心肌梗死后7天这种新形成的心肌组织并不明显。细胞内钙瞬变成像表明，新形成心肌中的心肌细胞与远端心肌形成功能性合胞体。
这些发现表明，心肌细胞周期激活可导致心肌梗死后心脏功能和形态的改善，可能代表了促进心肌再生的一种重要临床策略。
