Phosphoinositide kinases play key roles in norepinephrine- and angiotensin II-induced increase in phosphatidylinositol 4,5-bisphosphate and modulation of cardiac function.
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.
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.
Jia-Xi
JX
Xu
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.
Man
M
Si
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.
Hui-Ran
HR
Zhang
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.
Xing-Juan
XJ
Chen
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.
Xi-Dong
XD
Zhang
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.
Chuan
C
Wang
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.
Xiao-Na
XN
Du
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. Electronic address: zhanghl@hebmu.edu.cn.
Hai-Lin
HL
Zhang
D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D004195:Disease Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D058538:Phosphatidylinositol-4-Phosphate 3-Kinase / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019269:Phosphatidylinositol 4,5-Diphosphate; D000804:Angiotensin II; D058538:Phosphatidylinositol-4-Phosphate 3-Kinase; D009638:Norepinephrine
Cardiac Hypertrophy; G Protein-coupled Receptors (GPCR); Phosphatidylinositol Kinase; Phospholipid Metabolism; Signal Transduction