Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice.
Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice.
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DOI：
10.1161/jaha.115.001770
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发表时间：
2015-02-24
影响因子：
5.4
通讯作者：
Schäfer K
中科院分区：
文献类型：
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作者：
Gogiraju R;Xu X;Bochenek ML;Steinbrecher JH;Lehnart SE;Wenzel P;Kessel M;Zeisberg EM;Dobbelstein M;Schäfer K
慢性压力超负荷引起的心功能不全与细胞凋亡和心肌血管稀疏有关。我们研究了内皮细胞中肿瘤抑制基因p53的缺失是否可以阻止心脏肥大向心力衰竭的转变。通过将p53 fl/fl小鼠与在诱导型Tie 2启动子控制下表达Cre重组酶的小鼠杂交，产生具有内皮特异性p53缺失（End.p53-KO）的小鼠。用主动脉缩窄法诱导心肌肥厚。连续超声心动图测量结果显示，End.p53-KO小鼠的心脏功能得到改善，存活率也更高。End.p53-WT对照小鼠的心脏肥大与p53水平升高相关，而End.p53-KO小鼠的带状心脏表现出较低数量的凋亡内皮细胞和非内皮细胞，并改变了调节细胞周期进程（p21）、细胞凋亡（Puma）或增殖（Pcna）的基因的mRNA水平。观察到更高的心脏毛细血管密度和改善的心肌灌注，并且药理学抑制或p53基因缺失也促进了体外内皮发芽和体内后肢缺血后新血管形成。与End.p53-WT对照组相比，End.p53-KO小鼠的心脏纤维化明显减少，并且观察到参与细胞外基质产生和转换的p53调节基因（例如，Bmp-7、Ctgf或派-1）或参与控制间充质分化的转录因子的mRNA水平较低。我们的分析表明，p53在内皮细胞中的积累有助于血管稀疏和纤维化在慢性心脏压力超负荷，并建议，内皮细胞可能是一个治疗目标，以保持心脏功能在肥大。
Cardiac dysfunction developing in response to chronic pressure overload is associated with apoptotic cell death and myocardial vessel rarefaction. We examined whether deletion of tumor suppressor p53 in endothelial cells may prevent the transition from cardiac hypertrophy to heart failure. Mice with endothelial‐specific deletion of p53 (End.p53‐KO) were generated by crossing p53fl/fl mice with mice expressing Cre recombinase under control of an inducible Tie2 promoter. Cardiac hypertrophy was induced by transverse aortic constriction. Serial echocardiography measurements revealed improved cardiac function in End.p53‐KO mice that also exhibited better survival. Cardiac hypertrophy was associated with increased p53 levels in End.p53‐WT controls, whereas banded hearts of End.p53‐KO mice exhibited lower numbers of apoptotic endothelial and non‐endothelial cells and altered mRNA levels of genes regulating cell cycle progression (p21), apoptosis (Puma), or proliferation (Pcna). A higher cardiac capillary density and improved myocardial perfusion was observed, and pharmacological inhibition or genetic deletion of p53 also promoted endothelial sprouting in vitro and new vessel formation following hindlimb ischemia in vivo. Hearts of End.p53‐KO mice exhibited markedly less fibrosis compared with End.p53‐WT controls, and lower mRNA levels of p53‐regulated genes involved in extracellular matrix production and turnover (eg, Bmp‐7, Ctgf, or Pai‐1), or of transcription factors involved in controlling mesenchymal differentiation were observed. Our analyses reveal that accumulation of p53 in endothelial cells contributes to blood vessel rarefaction and fibrosis during chronic cardiac pressure overload and suggest that endothelial cells may be a therapeutic target for preserving cardiac function during hypertrophy.