Key Laboratory of Neural and Vascular Biology, Ministry of Education, the Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, and the Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
Key Laboratory of Neural and Vascular Biology, Ministry of Education, the Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, and the Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
J Biol Chem. 2014 Mar 7;289(10):6941-6948. doi: 10.1074/jbc.M113.527952. Epub 2014 Jan 21.
The seemly paradoxical Gq agonist-stimulated phosphoinositide production has long been known, but the underlying mechanism and its physiological significance are not known. In this study, we studied cardiac phosphoinositide levels in both cells and whole animals under the stimulation of norepinephrine (NE), angiotensin II (Ang II), and other physiologically relevant interventions. The results demonstrated that activation of membrane receptors related to NE or Ang II caused an initial increase and a later fall in phosphatidylinositol 4,5-bisphosphate (PIP2) levels in the primary cultured cardiomyocytes from adult rats. The possible mechanism underlying this increase in PIP2 was found to be through an enhanced activity of phosphatidylinositol 4-kinase IIIβ, which was mediated by an up-regulated interaction between phosphatidylinositol 4-kinase IIIβ and PKC; the increased activity of phosphatidylinositol 4-phosphate 5-kinase γ was also involved for NE-induced increase of PIP2. When the systolic functions of the NE/Ang II-treated cells were measured, a maintained or failed contractility was found to be correlated with a rise or fall in corresponding PIP2 levels. In two animal models of cardiac hypertrophy, PIP2 levels were significantly reduced in hypertrophic hearts induced by isoprenaline but not in those induced by swimming exercise. This study describes a novel mechanism for phosphoinositide metabolism and modulation of cardiac function.
长期以来，人们已经知道看似矛盾的 Gq 激动剂刺激的磷酯酰肌醇代谢产物的产生，但其中的机制及其生理意义尚不清楚。在这项研究中，我们研究了去甲肾上腺素（NE）、血管紧张素 II（Ang II）和其他生理相关干预刺激下细胞和整体动物的心脏磷酯酰肌醇水平。结果表明，与 NE 或 Ang II 相关的膜受体的激活导致成年大鼠原代培养心肌细胞中磷脂酰肌醇 4,5-二磷酸（PIP2）水平的初始增加和随后的下降。发现 PIP2 增加的可能机制是通过增强磷脂酰肌醇 4-激酶 IIIβ的活性来实现的，这种活性是通过磷脂酰肌醇 4-激酶 IIIβ与蛋白激酶 C 之间的上调相互作用介导的；NE 诱导的 PIP2 增加还涉及磷脂酰肌醇 4-磷酸 5-激酶 γ的活性增加。当测量 NE/Ang II 处理细胞的收缩功能时，发现收缩功能的维持或失败与相应的 PIP2 水平的升高或下降相关。在两种心肌肥厚动物模型中，异丙肾上腺素诱导的肥厚心脏中 PIP2 水平显著降低，但游泳运动诱导的肥厚心脏中 PIP2 水平没有降低。这项研究描述了磷酯酰肌醇代谢的新机制和心脏功能的调节。
