Minamino Tetsuo, Yujiri Toshiaki, Terada Naohiro, Taffet George E, Michael Lloyd H, Johnson Gary L, Schneider Michael D
Center for Cardiovascular Development and The DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3866-71. doi: 10.1073/pnas.062453699. Epub 2002 Mar 12.
Signaling via mitogen-activated protein kinases is implicated in heart failure induced by agonists for G protein-coupled receptors that act via the G protein Galphaq. However, this assertion relies heavily on pharmacological inhibitors and dominant-interfering proteins and not on gene deletion. Here, we show that endogenous cardiac MAPK/ERK kinase kinase-1 (MEKK1)/(MAP3K1), a mitogen-activated protein kinase kinase kinase, is activated by heart-restricted overexpression of Galphaq in mice. In cardiac myocytes derived from embryonic stem cells in culture, homozygous disruption of MEKK1 selectively impaired c-Jun N-terminal kinase activity in the absence or presence of phenlyephrine, a Galphaq-dependent agonist. Other terminal mitogen-activated protein kinases were unaffected. In mice, the absence of MEKK1 abolished the increase in cardiac mass, myocyte size, hypertrophy-associated atrial natriuretic factor induction, and c-Jun N-terminal kinase activation by Galphaq, and improved ventricular mechanical function. Thus, MEKK1 mediates cardiac hypertrophy induced by Galphaq in vivo and is a logical target for drug development in heart disease involving this pathway.
通过丝裂原活化蛋白激酶的信号传导与由通过G蛋白Gαq起作用的G蛋白偶联受体激动剂诱导的心力衰竭有关。然而，这一论断很大程度上依赖于药理学抑制剂和显性干扰蛋白，而非基因缺失。在此，我们表明内源性心脏丝裂原活化蛋白激酶/细胞外信号调节激酶激酶-1（MEKK1）/（MAP3K1），一种丝裂原活化蛋白激酶激酶激酶，在小鼠中通过心脏特异性过表达Gαq而被激活。在培养的源自胚胎干细胞的心肌细胞中，MEKK1的纯合缺失在有无苯肾上腺素（一种Gαq依赖性激动剂）的情况下选择性损害c-Jun氨基末端激酶活性。其他终末丝裂原活化蛋白激酶未受影响。在小鼠中，MEKK1的缺失消除了由Gαq引起的心脏质量增加、心肌细胞大小增加、肥大相关的心房利钠因子诱导以及c-Jun氨基末端激酶激活，并改善了心室机械功能。因此，MEKK1在体内介导由Gαq诱导的心肌肥大，并且是涉及该途径的心脏病药物开发的合理靶点。
