Apolipoprotein E-deletion potentiates endothelium-dependent relaxations to prostacyclin receptor activation in the mouse aorta

Abstract

Introduction: Nitric oxide (NO)-mediated relaxations of isolated arteries are blunted by ageing and high-fat diet, as well as by apolipoprotein E-deletion. Aims: The present study was designed to examine the prostacyclin receptor (IP)-mediated responses in the mouse aorta and the consequences of apolipoprotein E deletion on IP-mediated responses. Methods: Wild-type, ApoE-/-, ApoE-/-IP-/- mice (male, five-weeks old) were fed normal chow or high-fat diet during 29 weeks. Aortae were exposed to iloprost (IP receptor agonist), acetylcholine (muscarinic receptor agonist) and UK14304 (α2-adrenergic receptor agonist) and isometric tension was recorded in a Halpern-Mulvany myograph. Protein presences and cyclic nucleotide levels were measured by Western blotting and ELISA, respectively. Results: Iloprost induced endothelium-, nitric oxide synthase (eNOS)-dependent relaxations in aortae of young wild-type mice by activating IP receptors. Iloprost-induced relaxations were blunted in aortae of mice fed high-fat diet compared to age-matched ones fed normal chow; the blunting was restored by the antagonist of thromboxane-prostanoid (TP) receptors S18886. Apolipoprotein E was present in the plasma and aortae of wild-type (but not of ApoE-/-) mice, especially in the endothelium; its presence was augmented by the high-fat diet. In aortae of young ApoE-/- mice, iloprost-induced relaxations were larger than those in preparations of wild-type mice and were not affected by the high-fat diet. Iloprost did not induce relaxations in aortae of ApoE-/-IP-/- mice. However, acetylcholine- and UK14304-induced relaxations were blunted in the aortae of ApoE-/-IP-/- mice. Conclusion: Iloprost induces endothelium-, eNOS- and IP-dependent relaxations. High-fat diet favors the activation of TP receptors by iloprost causing contraction. Apolipoprotein E-deletion potentiates relaxations to IP receptor activation irrespective of age and diet. IP deletion blunts NO-mediated relaxations in mouse aorta.