AAV9-mediated VEGF-B Gene Transfer Improves Systolic Function in Progressive Left Ventricular Hypertrophy
AAV9-mediated VEGF-B Gene Transfer Improves Systolic Function in Progressive Left Ventricular Hypertrophy
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DOI：
10.1038/mt.2012.145
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发表时间：
2012-12-01
影响因子：
12.4
通讯作者：
Yla-Herttuala, Seppo
中科院分区：
文献类型：
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作者：
Huusko, Jenni;Lottonen, Line;Yla-Herttuala, Seppo
从代偿性肥大到心力衰竭的转变机制知之甚少，血管内皮生长因子（VEGF）在这一过程中的作用尚未完全阐明。我们测定了左心室肥厚（LVH）过程中VEGF及其相关受体的表达谱。将C57 BL小鼠暴露于横向主动脉缩窄（TAC），并在不同时间点（1天、2周、4周和10周）研究结果。在随后的心力衰竭（TAC后4周）中观察到明显的代偿期（TAC后2周）。有趣的是，VEGF-C和VEGF-D以及VEGF受体-3（VEGFR-3）在代偿性肥大中上调，而VEGF-B在心力衰竭中下调。在代偿期用腺相关病毒血清型9（AAV 9）-VEGF-B-186基因治疗4周后，由于血管生成、细胞凋亡的抑制和心肌细胞增殖的促进，心脏的功能得以保留。此外，在AAV 9-VEGF-B-186处理的小鼠中，朝向胎儿基因表达的遗传编程（心力衰竭中的已知现象）被部分逆转。结论VEGF-C和VEGF-D与代偿性LVH相关，AAV 9-VEGF-B186基因转移可以挽救衰竭心脏的功能，延缓向心力衰竭的转变。收稿日期：2012年3月23日;接受日期：2012年6月26日;提前在线发布日期：2012年10月23日。doi：10.1038/mt.2012.145
Mechanisms of the transition from compensatory hypertrophy to heart failure are poorly understood and the roles of vascular endothelial growth factors (VEGFs) in this process have not been fully clarified. We determined the expression profile of VEGFs and relevant receptors during the progression of left ventricular hypertrophy (LVH). C57BL mice were exposed to transversal aortic constriction (TAC) and the outcome was studied at different time points (1 day, 2, 4, and 10 weeks). A clear compensatory phase (2 weeks after TAC) was seen with following heart failure (4 weeks after TAC). Interestingly, VEGF-C and VEGF-D as well as VEGF receptor-3 (VEGFR-3)were upregulated in the compensatory hypertrophy and VEGF-B was downregulated in the heart failure. After treatment with adeno-associated virus serotype 9 (AAV9)-VEGF-B-186 gene therapy in the compensatory phase for 4 weeks the function of the heart was preserved due to angiogenesis, inhibition of apoptosis, and promotion of cardiomyocyte proliferation. Also, the genetic programming towards fetal gene expression, a known phenomenon in heart failure, was partly reversed in AAV9-VEGF-B-186-treated mice. We conclude that VEGF-C and VEGF-D are associated with the compensatory LVH and that AAV9-VEGF-B186 gene transfer can rescue the function of the failing heart and postpone the transition towards heart failure. Received 23 March 2012; accepted 26 June 2012; advance online publication 23 October 2012. doi:10.1038/mt.2012.145