期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 301, 期 3, 页码 H881-H887出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00305.2011
关键词
benzoyl benzoyl adenosine 5 '-triphosphate; cardioprotection; G protein-coupled receptors; P2X(7) receptor; hemichannels; phospho-Akt; sphingosine 1-phosphate
资金
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development
Vessey DA, Li L, Kelley M. P2X(7) receptor agonists pre- and postcondition the heart against ischemia-reperfusion injury by opening pannexin-1/P2X(7) channels. Am J Physiol Heart Circ Physiol 301: H881-H887, 2011. First published June 17, 2011; doi:10.1152/ajpheart.00305.2011.-Protection of the heart from ischemia-reperfusion injury can be achieved by ischemic preconditioning and ischemic postconditioning. Previous studies revealed that a complex of pannexin-1 with the P2X(7) receptor forms a channel during ischemic preconditioning and ischemic postconditioning that results in the release of endogenous cardioprotectants. ATP binds to P2X(7) receptors, inducing the formation of a channel in association with pannexin-1. We hypothesized that this channel would provide a pathway for the release of these same cardioprotectants. Preconditioning-isolated perfused rat hearts with 0.4 mu M ATP preceding 40 min of ischemia minimized infarct size upon subsequent reperfusion (5% of risk area) and resulted in >80% recovery of left ventricular developed pressure. Postconditioning with ATP after ischemia during reperfusion was also protective (6% infarct and 72% recovery of left ventricular developed pressure). Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X(7) receptors (brilliant blue G and A438079) blocked ATP pre- and postconditioning, indicating that ATP protection was elicited via the opening of a pannexin-1/P2X(7) channel. An antagonist of binding of the endogenous cardioprotectant sphingosine 1-phosphate to its G protein-coupled receptor diminished protection by ATP, which is also consistent with an ATP-dependent release of cardioprotectants. Suramin, an antagonist of binding of ATP (and ADP) to P2Y receptors, was without effect on ATP protection. Benzoyl benzoyl-ATP, a more specific P2X(7) agonist, was also a potent pre- and postconditioning agent and sensitive to blockade by pannexin-1/P2X(7) channel antagonists. The data point out for the first time the potential of P2X(7) agonists as cardioprotectants.
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