Research Center for Cardiovascular Regenerative Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing 100037, China.
Int J Cardiol. 2010 Sep 3;143(3):414-23. doi: 10.1016/j.ijcard.2009.03.111. Epub 2009 Jul 24.
The purpose of this study was to gain a better understanding of molecular changes associated with the beneficial reverse remodeling through heterotopic transplantation model of rat hypertrophic hearts.
Stable cardiac hypertrophy was induced by abdominal aortic constriction (AAC) in Lewis rats (6 weeks). Left ventricular (LV) pressure unloading was induced by heterotopic transplantation of hypertrophic hearts (AAC-HT) (2 weeks). We measured heart weight (HW), LV weight (LVW) and the LV-to-final body weight ratio (LVW/BW). Cross-sectional areas of cardiomyocyte and collagen content were assessed by hematoxylin/eosin staining and picrosirius red staining, respectively. We further analyzed the signaling pathways of mitogen-activated protein kinases (MAPKs), Akt/GSK3β, NF-κB, metalloproteinase-2,9 (MMP-2, 9) and tissue inhibitors of metalloproteinase-1 (TIMP-1) by Western blot.
The HW, LVW and LVW/BW in AAC hearts were higher than normal hearts, but the transplanted hearts showed a significant reduction in HW, LVW and LVW/BW compared to AAC hearts. Unloading induced a decrease in cardiomyocyte size and an increase in collagen content in AAC-HT hearts. A significant decrease in phosphorylation of p44/p42 MAP kinases (ERK), Akt, GSK3β and NF-κB was detected in AAC-HT hearts, but the phosphorylation of p38 MAP kinase and Jun-N-terminal kinase (JNK) was not changed. MMP-2, MMP-9 and TIMP-1 activity also increased accompanied by unloading.
Pressure unloading of the hypertrophic heart caused a reverse remodeling through regulating the ERK, Akt/GSK3β, and NFκB signal pathways, revealing these as potential target pathways for reversal of LV hypertrophy.
本研究旨在通过大鼠肥厚心脏异位移植模型，深入了解与有益的逆重构相关的分子变化。
通过腹主动脉缩窄（AAC）在 Lewis 大鼠中诱导稳定的心脏肥厚（6 周）。通过异位移植肥厚心脏（AAC-HT）（2 周）诱导左心室（LV）压力卸载。我们测量了心脏重量（HW）、LV 重量（LVW）和 LV 与最终体重比（LVW/BW）。通过苏木精/伊红染色和苦味酸天狼猩红染色分别评估心肌细胞的横截面积和胶原含量。我们进一步通过 Western blot 分析了丝裂原激活蛋白激酶（MAPKs）、Akt/GSK3β、NF-κB、基质金属蛋白酶-2、9（MMP-2、9）和基质金属蛋白酶组织抑制剂-1（TIMP-1）的信号通路。
AAC 心脏的 HW、LVW 和 LVW/BW 高于正常心脏，但与 AAC 心脏相比，移植心脏的 HW、LVW 和 LVW/BW 明显减少。卸载导致 AAC-HT 心脏的心肌细胞大小减小，胶原含量增加。在 AAC-HT 心脏中检测到 p44/p42 MAP 激酶（ERK）、Akt、GSK3β 和 NF-κB 的磷酸化显著减少，但 p38 MAP 激酶和 Jun-N-末端激酶（JNK）的磷酸化没有改变。MMP-2、MMP-9 和 TIMP-1 活性也随卸载而增加。
肥厚心脏的压力卸载通过调节 ERK、Akt/GSK3β 和 NFκB 信号通路引起逆重构，表明这些通路是逆转 LV 肥厚的潜在靶点。
