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    The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP-receptor


    Lawler, Orlaith A. and Miggin, Sinead and Kinsella, B. Therese (2001) The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP-receptor. British of Pharmacology, 132 (8). ISSN 0007-1188

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    Abstract

    The prostanoid-IP receptor may be unique among G protein coupled receptors in that it is isoprenylated. In this study, we investigated the effects of the statins lovastatin and cerivastatin on signalling by the mouse (m) IP and the human (h) IP receptors, over-expressed in human embryonic kidney (HEK) 293 cells and by the hIP receptor, endogenously expressed in human erythroleukaemia cells. Both statins significantly reduced IP receptor-mediated cyclic AMP generation and intracellular calcium ([Ca2+]i) mobilization in a time and concentration dependent manner but had no effect on signalling by the non-isoprenylated β2 adrenergic receptor or by the human prostanoid-TP receptor isoforms. Cerivastatin (IC50, 50 – 90 nM) was significantly more potent than lovastatin (IC50, 0.80 – 4.2 μM) in inhibiting IP receptor signalling. Whereas IC50 values indicated that the hIP receptor was significantly more sensitive than the mIP receptor to the statins, the extent of inhibition of cyclic AMP generation by the mIP receptor was significantly greater than that of the hIP receptor to either statin, even at the highest concentrations used. Pretreatment with either statin significantly reduced IP receptor mediated desensitization of signalling by the h.TPα, but not by the h.TPβ, receptor isoform. These data generated in whole cells point to the possibility that statin therapy may interfere with IP receptor signalling in vivo; such interference may be extenuated under conditions where circulating statin levels are elevated and may account, in part, for some of the pleiotropic affects of the statins not attributed solely to their lipid lowering properties.

    Item Type: Article
    Keywords: Prostacyclin; lovastatin; cerivastatin; isoprenylation; prostaglandin I2; receptor; thromboxane A2; statins; cholesterol; atherosclerosis;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12646
    Identification Number: https://doi.org/10.1038/sj.bjp.0704033
    Depositing User: Sinead Miggin
    Date Deposited: 27 Mar 2020 11:45
    Journal or Publication Title: British of Pharmacology
    Publisher: Wiley
    Refereed: Yes
    URI:

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