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A pirinixic acid derivative (LP105) inhibits murine 5‐lipoxygenase activity and attenuates vascular remodelling in a murine model of aortic aneurysm
Author(s) -
Revermann M,
Mieth A,
Popescu L,
Paulke A,
Wurglics M,
Pellowska M,
Fischer AS,
Steri R,
Maier TJ,
Schermuly RT,
Geisslinger G,
SchubertZsilavecz M,
Brandes RP,
Steinhilber D
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01321.x
Subject(s) - aortic aneurysm , lipoxygenase , chemistry , derivative (finance) , aorta , pharmacology , medicine , biochemistry , enzyme , financial economics , economics
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.