title: A pirinixic acid derivative (LP105) inhibits murine 5-lipoxygenase activity and attenuates vascular remodelling in a murine model of aortic aneurysm.
abstract: BACKGROUND AND PURPOSE Arachidonic acid derivatives play a central role in inflammation processes. Arachidonic acid is metabolized by several enzymes, particularly cyclooxygenases (COX), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E-synthase-1 (mPGES-1) to pro-inflammatory mediators. EXPERIMENTAL APPROACH We determined the effect of LP105, a pirinixic acid derivative which acts as inhibitor of 5-LOX, COX and mPGES-1, on aortic aneurysm development in mice and on 5-LOX activity in murine monocytes. KEY RESULTS In a monocyte cell line (RAW264.7), LP105 inhibited 5-LOX in whole cells (IC(50) : 1-3 µM) and in supernatants (IC(50) : ∼10 µM). Oral administration of LP105 to mice resulted in therapeutic tissue and plasma levels. Aortic aneurysms were induced in ApoE(-/-) mice by angiotensin II (AngII) and LP105 (5 mg·day(-1) per animal) was co-administered to a subgroup. Compared with animals receiving AngII alone, the LP105+AngII group showed a lower heart rate, a trend towards reduced heart to body weight ratio but similar hypertensive responses. AngII alone significantly increased aortic weight and diameter but co-treatment with LP105+AngII prevented these changes. LC/MS-MS studies revealed increased 15-hydroxytetraenoic acid (15-HETE) and 14,15-epoxyeicosatrienoic acid (14,15-EET) plasma levels in LP105-treated animals. In the murine kidney, mRNAs of EET-generating or metabolizing enzymes and of 5-LOX and 15-LOX were unaffected by LP105. LP105 also did not inhibit the EET-metabolizing soluble epoxide hydrolase. CONCLUSIONS AND IMPLICATIONS LP105 was a potent inhibitor of monocyte 5-LOX and reduced AngII-induced vascular remodelling in mice. A shift of arachidonic acid metabolism to the protective EET pathway may contribute to the beneficial effects of LP105.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Revermann
authors.forename: A
authors.initials: A
authors.lastname: Mieth
authors.forename: L
authors.initials: L
authors.lastname: Popescu
authors.forename: A
authors.initials: A
authors.lastname: Paulke
authors.forename: M
authors.initials: M
authors.lastname: Wurglics
authors.forename: M
authors.initials: M
authors.lastname: Pellowska
authors.forename: A S
authors.initials: AS
authors.lastname: Fischer
authors.forename: R
authors.initials: R
authors.lastname: Steri
authors.forename: T J
authors.initials: TJ
authors.lastname: Maier
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
authors.forename: M
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: R P
authors.initials: RP
authors.lastname: Brandes
authors.forename: D
authors.initials: D
authors.lastname: Steinhilber
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000378:metabolism / Q000473:pathology*; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002319:Cardiovascular System / Q000187:drug effects; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000097:blood / Q000378:metabolism; D007279:Injections, Subcutaneous; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002316:Cardiotonic Agents; D016861:Cyclooxygenase Inhibitors; C569587:LP105 compound; D016859:Lipoxygenase Inhibitors; D011743:Pyrimidines; D000804:Angiotensin II; C006253:pirinixic acid; D001094:Arachidonate 5-Lipoxygenase; D004851:Epoxide Hydrolases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse