Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy
Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy
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DOI：
10.1096/fj.07-100966
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Rupnick, Maria A.
中科院分区：
文献类型：
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作者：
Dallabrida, Susan M.;Ismail, Nesreen S.;Rupnick, Maria A.
血管生成素被认为是通过Tie2受体特异性的内皮细胞。我们发现血管生成素-1(Ang1)也与心肌细胞(CMS)上的整合素相互作用以提高存活率。由于Ang1单体结合并激活整合素(而不是Tie2)，我们确定了它们在体内的功能。我们检测了生理性和病理性心脏重塑过程中单体和多聚体的表达，以及在苯肾上腺素诱导的心肌肥厚中Ang1单体的过度表达。心脏Ang1水平(mRNA和蛋白)在出生后发育过程中升高，并随着苯肾上腺素诱导的心肌肥厚而下降，而Tie2的磷酸化没有变化。我们发现，心脏重塑过程中的大部分或全部变化都是在单体中发生的，这为Tie2活性不变提供了一个解释。心脏组织含有丰富的Ang1单体和很少的多聚体(Western Blotting)。我们产生了产生Ang1单体(Ang1-256)的质粒，将它们注射到小鼠体内，并证实了心脏的表达(免疫组织化学、RT-PCR)。Ang1单体定位于CMS、血管内皮细胞和平滑肌细胞。在苯肾上腺素诱导的心肌肥厚中，Ang1-256降低了左心室(LV)/胫骨比值、胎儿基因表达(心钠素和脑钠素、骨骼肌动蛋白、β-肌球蛋白重链)和纤维化(III型胶原)，增加了左室存活信号(AKT、MAPK(P42/44)和AMPK(T172)。然而，Tie2的磷酸化没有变化。Ang1-256增加了整合素连接的激酶，这是整合素信号和心脏健康的关键调节因子。总而言之，这些结果。
Angiopoietins were thought to be endothelial cell-specific via the tie2 receptor. We showed that angiopoietin-1 (ang1) also interacts with integrins on cardiac myocytes (CMs) to increase survival. Because ang1 monomers bind and activate integrins (not tie2), we determined their function in vivo. We examined monomer and multimer expressions during physiological and pathological cardiac remodeling and overexpressed ang1 monomers in phenylephrine-induced cardiac hypertrophy. Cardiac ang1 levels (mRNA, protein) increased during postnatal development and decreased with phenylephrine-induced cardiac hypertrophy, whereas tie2 phosphorylations were unchanged. We found that most or all of the changes during cardiac remodeling were in monomers, offering an explanation for unchanged tie2 activity. Heart tissue contains abundant ang1 monomers and few multimers (Western blotting). We generated plasmids that produce ang1 monomers (ang1-256), injected them into mice, and confirmed cardiac expression (immunohistochemistry, RT-PCR). Ang1 monomers localize to CMs, smooth muscle cells, and endothelial cells. In phenylephrine-induced cardiac hypertrophy, ang1-256 reduced left ventricle (LV)/tibia ratios, fetal gene expressions (atrial and brain natriuretic peptides, skeletal actin, beta-myosin heavy chain), and fibrosis (collagen III), and increased LV prosurvival signaling (akt, MAPK(p42/44)), and AMPK(T172). However, tie2 phosphorylations were unchanged. Ang1-256 increased integrin-linked kinase, a key regulator of integrin signaling and cardiac health. Collectively, these results.