Dataset Information

Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts.

ABSTRACT:

Objective

Prostacyclin and thromboxane mediate opposing cardiovascular actions through receptors termed IP and TP, respectively. When dimerized with IP, the TP shifts to IP-like function. IP localizes to cholesterol-enriched membrane rafts, but TP and IPTP heterodimer localization is not defined. We examined these receptors' membrane localization and the role of rafts in receptor function.

Methods and results

Microdomain distribution of IP, TP, and IPTP heterodimers was examined in COS-7 cells by measuring energy transfer from renilla luciferase-fused receptors to fluorescently labeled rafts. IP raft association was confirmed. TP was raft excluded, but redistributed to rafts upon dimerization with IP. Signaling of the IP and IPTP heterodimer, but not TP alone, was suppressed after raft disruption by cholesterol depletion. Cholesterol enrichment also selectively suppressed IP and IPTP function. Native IP and IPTP signaling in smooth muscle cells and macrophages were similarly sensitive to cholesterol manipulation, whereas macrophages from hypercholesterolemic mice displayed suppressed IP and IPTP function.

Conclusions

IP and TP function within distinct microdomains. Raft incorporation of TP in the IPTP heterodimer likely facilitates its signaling shift. We speculate that changes in IP and IPTP signaling after perturbation of membrane cholesterol may contribute to cardiovascular disease associated with hypercholesterolemia.

SUBMITTER: Ibrahim S

PROVIDER: S-EPMC3533363 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts.

Ibrahim Salam S McCartney Ann A Markosyan Nune N Smyth Emer M EM

Arteriosclerosis, thrombosis, and vascular biology 20121115 1

<h4>Objective</h4>Prostacyclin and thromboxane mediate opposing cardiovascular actions through receptors termed IP and TP, respectively. When dimerized with IP, the TP shifts to IP-like function. IP localizes to cholesterol-enriched membrane rafts, but TP and IPTP heterodimer localization is not defined. We examined these receptors' membrane localization and the role of rafts in receptor function.<h4>Methods and results</h4>Microdomain distribution of IP, TP, and IPTP heterodimers was examined i ...[more]

PMID: 23162015

Similar Datasets

Project description:BackgroundPregnancy increases the risk of morbidity and mortality in sickle cell disease. We previously showed pregnant women with sickle cell disease to have a relatively low plasma renin concentration in late pregnancy, associated with a lack of the expected plasma volume expansion. We hypothesized this to be due to increased systemic vascular resistance through an imbalance between the vasodilator prostacyclin and vasoconstrictor thromboxane, associated with decreased glomerular filtration rate (GFR).ObjectiveTo compare estimated prostacyclin, thromboxane and GFR in non-pregnant and pregnant women with hemoglobin SS (HbSS) and AA (HbAA).Study designFour groups of 20 normotensive, nulliparous women were studied in Lagos, Nigeria: pregnant HbSS or HbAA women at 36-40 weeks gestation; non-pregnant HbSS and HbAA controls. We measured stable metabolites of prostacyclin and thromboxane A2 by enzyme-linked immunosorbent assay; GFR using the Cockcroft-Gault equation. Data analysis was by independent (Student's) t-test or Mann-Whitney U test for comparisons between any two groups of continuous variables, univariate ANOVA for multiple groups and Pearson's correlation coefficient for degree of association between variables.ResultsHbSS women had lower serum 6-keto-PGF1α concentrations than HbAA, whether pregnant or non-pregnant (P<0.001; P<0.004 respectively). Conversely, pregnant HbSS women had higher serum TxB2 (P<0.001); non-pregnant HbSS women had non-significantly higher TxB2 concentrations. The 6-keto-PGF1α:TxB2 ratio was markedly increased (pro-vasodilatory) in HbAA pregnancy (P<0.001) but reduced in HbSS pregnancy (P = 0.037). GFRs (mL/min) were higher in non-pregnant HbSS than HbAA (P<0.008) but only marginally raised in HbSS women in late pregnancy (P = 0.019) while markedly raised in HbAA pregnancy (P<0.001).ConclusionThe lower ratio of prostacyclin-thromboxane metabolites in HbSS pregnancy may indicate endothelial damage and an increased tendency to vasoconstriction and clotting. If confirmed by subsequent longitudinal studies, interventions to increase prostacyclin and reduce thromboxane, such as low dose aspirin, may be potentially useful in their management.

Dataset Information

Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts.

Objective

Methods and results

Conclusions

Publications

Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets