Diacylglycerol and fatty acids synergistically increase cardiomyocyte contraction via activation of PKC.
Diacylglycerol and fatty acids synergistically increase cardiomyocyte contraction via activation of PKC.
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二酰甘油和脂肪酸通过激活 PKC 协同增加心肌细胞收缩。
DOI：
10.1152/ajpheart.2000.279.1.h26
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Walker,JW
中科院分区：
文献类型：
--
作者：
Pi,Y;Walker,JW
脂质信号通路被认为在将细胞外信号转导为心肌收缩反应中起着重要作用。两种假定的脂质信使，二甘油三酯和花生四烯酸，可以通过不同的磷脂酶在不同的信号通路中产生，但某些刺激会使它们平行升高。我们测试了这些脂质通过激活蛋白激酶C （PKC）作为心室肌细胞信使的假设。在之前的工作中，我们证明了二酰基甘油类似物二辛烷酰甘油（diC8）可以刺激或抑制肌细胞抽搐，这取决于它是如何应用的。在这里，我们报道了花生四烯酸和其他不饱和脂肪酸（UFA），在浓度太低而无法直接作用时，协同增强dic8的刺激作用，并将dic8的抑制作用转化为对肌细胞抽搐的刺激。细胞内Ca2+瞬态变化与抽搐幅度平行，表明这些脂质调节Ca2+稳态。顺式ufa还与PKC激活剂phorbol 12-肉豆蔻酸酯13-醋酸酯协同作用，促进正性肌力反应。反应被PKC拮抗剂chelerythrine chloride， bisindolylmale酰亚胺和Gö-6976阻断。dic8和花生四烯酸也在完整肌细胞中协同易位PKC-ε和PKC-α。我们认为PKC在心脏中整合了二酰基甘油和顺式ufa信号，导致正性肌力机制的优先激活。
Lipid signaling pathways are thought to play a prominent role in transducing extracellular signals into contractile responses in cardiac muscle. Two putative lipid messengers, diacyglycerol and arachidonic acid, can be generated via distinct phospholipases in separate signaling pathways, but certain stimuli cause them to be elevated in parallel. We tested the hypothesis that these lipids function as comessengers in ventricular myocytes by activating protein kinase C (PKC). In previous work, we demonstrated that the diacylglycerol analog dioctanoylglycerol (diC8) can be stimulatory or inhibitory toward myocyte twitches depending on how it is applied. Here we report that arachidonic acid and othercis-unsaturated fatty acids (UFA), at concentrations too low for direct effects, synergistically enhance the stimulatory effects of diC8and convert inhibitory effects of diC8into stimulation of myocyte twitches. Intracellular Ca2+transients changed in parallel with twitch amplitude, suggesting regulation of Ca2+homeostasis by these lipids.cis-UFA also interacted synergistically with the PKC activator phorbol 12-myristate 13-acetate to promote positive inotropic responses. Responses were blocked by the PKC antagonists chelerythrine chloride, bisindolylmaleimide, and Gö-6976. DiC8and arachidonic acid also synergistically translocated PKC-ε and PKC-α in intact myocytes. We propose that PKC integrates diacylglycerol andcis-UFA signals in the heart, resulting in preferential activation of positive inotropic mechanisms.