Abstract
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.
Highlights
The mechanism and significance of phosphoinositide metabolism during heart stress stimulations are not clear
PIP2 Level Is Correlated with the Cardiac Function—we studied whether the NE- and angiotensin II (Ang II)-induced effects on PIP2 turnover are associated with their effects on the function of cardiomyocytes
In this study, we demonstrated that activation of ␣1 receptor or AT1 receptor with NE and Ang II, respectively, did not reduce but increased cellular PIP2 levels in primary cultured adult rat cardiomyocytes
Summary
The mechanism and significance of phosphoinositide metabolism during heart stress stimulations are not clear. We describe an agonist-induced increase in both PIP and PIP2 levels and present a novel mechanism for these increases to be the result of the enhanced activity of PI4KIII, mediated by an up-regulated interaction between PI4KIII and PKC; for NE, an increased activity of phosphatidylinositol 4-phosphate 5-kinase ␥ was involved. This enhanced PIP2 turnover is correlated with maintained cardiac systolic function in stimulated cardiac hypertrophy
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