Thymosin beta4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo.
Thymosin beta4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo.
复制标题
胸腺素 beta4 介导的 PKC 激活对于成年小鼠体内启动胚胎冠状动脉发育程序和心外膜祖细胞激活至关重要。
DOI：
10.1016/j.yjmcc.2009.01.017
复制
发表时间：
2009-05
影响因子：
5
通讯作者：
DiMaio, J. Michael
中科院分区：
文献类型：
--
作者：
Bock-Marquette, Ildiko;Shrivastava, Santwana;Pipes, G. C. Teg;Thatcher, Jeffrey E.;Blystone, Allissa;Shelton, John M.;Galindo, Cristi L.;Melegh, Bela;Srivastava, Deepak;Olson, Eric N.;DiMaio, J. Michael
缺氧性心脏病是全世界致残和死亡的主要原因。由于成年哺乳动物的心脏在缺氧后不能再生，因此尝试改变这种缺陷是至关重要的。正如斑马鱼所证明的那样，对胚胎发育程序的回忆可能是成功的关键。由于胸腺酶β4 （TB4）有利于心肌细胞存活，对胚胎冠状动脉发育至关重要，我们假设它重新激活胚胎发育程序，并启动成年哺乳动物心外膜祖细胞动员。我们发现TB4刺激成人冠状动脉内皮细胞的毛细血管样管形成，并增加胚胎内皮细胞的体外迁移和增殖。血管/心外膜物质（Bves）表达细胞的增加伴随着VEGF、Flk-1、TGF-β、FGFR-2、FGFR-4、FGF-17和β-Catenin表达的升高，以及Tbx-18和Wt-1阳性心肌祖细胞的增加，提示成人心外膜胚胎程序的全器官回忆。TB4还能在体外和体内积极调节肉豆油酰基化富丙氨酸C激酶底物（Marcks）的表达和磷酸化，Marcks是蛋白激酶C （PKC）活性的直接底物和指标。PKC抑制显著降低TB4引起的心外膜增厚、毛细血管生长和心肌祖细胞数量。我们的研究结果表明，TB4是第一个已知的能够在全身给药后激活成年哺乳动物心脏胚胎冠状动脉发育程序的分子，PKC在这一过程中起着重要作用。
Hypoxic heart disease is a predominant cause of disability and death worldwide. Since adult mammalian hearts are incapable of regeneration after hypoxia, attempts to modify this deficiency are critical. As demonstrated in zebrafish, recall of the embryonic developmental program may be the key to success. Because thymosin β4 (TB4) is beneficial for myocardial cell survival and essential for coronary development in embryos, we hypothesized that it reactivates the embryonic developmental program and initiates epicardial progenitor mobilization in adult mammals. We found that TB4 stimulates capillary-like tube formation of adult coronary endothelial cells and increases embryonic endothelial cell migration and proliferation in vitro. The increase of blood vessel/epicardial substance (Bves) expressing cells accompanied by elevated VEGF, Flk-1, TGF-β, FGFR-2, FGFR-4, FGF-17 and β-Catenin expression and increase of Tbx-18 and Wt-1 positive myocardial progenitors suggested organ-wide recall of the embryonic program in the adult epicardium. TB4 also positively regulated the expression and phosphorylation of myristoylated alanine-rich C-kinase substrate (Marcks), a direct substrate and indicator of protein kinase C (PKC) activity in vitro and in vivo. PKC inhibition significantly reduced TB4 initiated epicardial thickening, capillary growth and the number of myocardial progenitors. Our results demonstrate that TB4 is the first known molecule capable of organ-wide activation of the embryonic coronary developmental program in the adult mammalian heart after systemic administration and that PKC plays a significant role in the process.
登录
查看更多内容
影响因子：
2.7
作者：
RUNYAN, RB;MARKWALD, RR
通讯作者：
MARKWALD, RR
影响因子：
2.5
作者：
Smith, Travis K.;Bader, David M.
通讯作者：
Bader, David M.
影响因子：
64.8
作者：
Laugwitz, KL;Moretti, A;Chien, KR
通讯作者：
Chien, KR
影响因子：
64.8
作者：
THELEN, M;ROSEN, A;ADEREM, A
通讯作者：
ADEREM, A
DOI：
10.1073/pnas.2132126100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Oh, H;Bradfute, SB;Schneider, MD
通讯作者：
Schneider, MD