Canopy 2 attenuates the transition from compensatory hypertrophy to dilated heart failure in hypertrophic cardiomyopathy
Canopy 2 attenuates the transition from compensatory hypertrophy to dilated heart failure in hypertrophic cardiomyopathy
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DOI：
10.1093/eurheartj/ehv294
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发表时间：
2015-10-01
影响因子：
39.3
通讯作者：
Li, Ren-Ke
中科院分区：
文献类型：
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作者：
Guo, Jian;Mihic, Anton;Li, Ren-Ke
血管新生和心肌细胞过度生长之间的不匹配可能是控制适应性肥大向心力衰竭转变的关键机制。Canopy 2（CNPY 2）是一种分泌型的HIF-1 α调节的血管生成因子。由于血管生成因子在心肌肥厚的发展中起着重要作用，我们使用过表达人CNPY 2的心脏特异性转基因（TG）小鼠研究CNPY 2在慢性心力衰竭发展过程中的分子和功能变化中的作用。通过横主动脉缩窄（TAC）在TG和野生型（WT）小鼠中诱导心肌病。WT小鼠在TAC后4周出现显著的心室肥大，在12周出现严重的扩张和心力衰竭。然而，TG小鼠保留了更好的心脏结构和功能，不太严重的心室扩张，并显着减少心脏细胞凋亡和纤维化后TAC。与WT小鼠相比，TG小鼠中过量的CNPY 2可防止TAC损伤后长达12周的血管系统的显著损失，从而产生更好的局部心肌环境，促进肌细胞存活并防止过度的基质重塑。TG小鼠TAC后内源性肿瘤抑制因子p53的积累较少，表明内源性激活p53介导的HIF-1 α的抑制，和Cnpy 2减少在TG小鼠与WT controls.Conclusion我们的研究表明，内源性小鼠Cnpy 2的下调和p53介导的HIF-1 α抑制在晚期肥大发育之间的相关性。额外的CNPY 2减弱了从代偿性肥大反应到适应不良的心室扩张和心力衰竭的转变。
Aims A mismatch between adequate angiogenesis and overgrowth of myocytes may be a critical mechanism controlling the transition from adaptive hypertrophy to heart failure. Canopy 2 (CNPY2) was recently identified as a secreted, HIF-1 alpha-regulated angiogenic growth factor. As angiogenic factors play important roles in the development of myocardial hypertrophy, we investigated the role of CNPY2 in molecular and functional changes during development of chronic heart failure using cardiac-specific transgenic (TG) mice that overexpress human CNPY2.Methods and results We generated TG mice that constitutively express CNPY2 in the myocardium. Cardiomyopathywas induced in TG and wild-type (WT) mice by transverse aortic constriction (TAC). WT mice developed significant ventricular hypertrophy at 4 weeks and severe dilatation and heart failure at 12 weeks after TAC. However, TG mice preserved much better cardiac structure and function, with less severe ventricular dilatation and markedly reduced cardiac apoptosis and fibrosis following TAC. Excess CNPY2 in TG mice prevented significant loss of vasculature up to 12 weeks after TAC injury, resulting in a better local myocardial environment that facilitated myocyte survival and prevented excessive matrix remodelling compared with WT mice. TG mice had less accumulation of endogenous tumor suppressor p53 after TAC, indicating intrinsic activation of the p53-mediated repression of HIF-1 alpha, and Cnpy2 was diminished in TG mice compared with WT controls.Conclusion Our study showed a correlation between downregulation of endogenous mouse Cnpy2 and p53-mediated HIF-1 alpha inhibition during late-stage hypertrophic development. Additional CNPY2 attenuated the transition from compensatory hypertrophic response to maladaptive ventricular dilatation and heart failure.