Wu G, Toyokawa T, Hahn H, Dorn G W
Division of Cardiology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
J Biol Chem. 2000 Sep 29;275(39):29927-30. doi: 10.1074/jbc.C000380200.
The epsilon isoform of protein kinase C (PKC) has a critical cardiotrophic function in normal postnatal developing heart as demonstrated by cardiac-specific transgenic expression of epsilonPKC-selective translocation inhibitor (epsilonV1) and activator (psiepsilonRACK) peptides (Mochly-Rosen, D., Wu, G., Hahn, H., Osinska, H., Liron, T., Lorenz, J. N., Robbins, J., and Dorn, G. W., II (2000) Circ. Res. 86, 1173-1179). To define the role of epsilonPKC signaling in pathological myocardial hypertrophy, epsilonV1 or psiepsilonRACK were co-expressed in mouse hearts with Galpha(q), a PKC-linked hypertrophy signal transducer. Compared with Galpha(q) overexpression alone, co-expression of psiepsilonRACK with Galpha(q) increased epsilonPKC particulate partitioning by 30 +/- 2%, whereas co-expression of epsilonV1 with Galpha(q) reduced particulate-associated epsilonPKC by 22 +/- 1%. Facilitation of epsilonPKC translocation by psiepsilonRACK in Galpha(q) mice improved cardiac contractile function measured as left ventricular fractional shortening (30 +/- 3% Galpha(q) versus 43 +/- 2% psiepsilonRACK/Galpha(q), p < 0.05). Conversely, inhibition of epsilonPKC by epsilonV1 modified the Galpha(q) nonfailing hypertrophy phenotype to that of a lethal dilated cardiomyopathy. These opposing effects of epsilonPKC translocation activation and inhibition in Galpha(q) hypertrophy indicate that epsilonPKC signaling is a compensatory event in myocardial hypertrophy, rather than a pathological event, and support the possible therapeutic efficacy of selective epsilonPKC translocation enhancement in cardiac insufficiency.
蛋白激酶C（PKC）的ε亚型在出生后正常发育的心脏中具有关键的心肌营养功能，这已通过εPKC选择性易位抑制剂（εV1）和激活剂（ψεRACK）肽的心脏特异性转基因表达得到证实（莫赫利 - 罗森，D.，吴，G.，哈恩，H.，奥辛斯卡，H.，利龙，T.，洛伦兹，J.N.，罗宾斯，J.，以及多恩，G.W.，II（2000年）《循环研究》86卷，1173 - 1179页）。为了确定εPKC信号在病理性心肌肥大中的作用，将εV1或ψεRACK与Gαq（一种与PKC相关的肥大信号转导分子）在小鼠心脏中共同表达。与单独过表达Gαq相比，ψεRACK与Gαq共同表达使εPKC颗粒分配增加了30±2%，而εV1与Gαq共同表达使颗粒相关的εPKC减少了22±1%。ψεRACK在Gαq小鼠中促进εPKC易位改善了心脏收缩功能，以左心室缩短分数衡量（Gαq为30±3%，ψεRACK/Gαq为43±2%，p<0.05）。相反，εV1对εPKC的抑制将Gαq非衰竭性肥大表型改变为致死性扩张型心肌病的表型。εPKC易位激活和抑制在Gαq肥大中的这些相反作用表明，εPKC信号是心肌肥大中的一种代偿性事件，而非病理性事件，并支持选择性增强εPKC易位在心脏功能不全中可能具有的治疗效果。
