TY - JOUR T1 - A novel orally available delta-5 desaturase inhibitor prevents atherosclerotic lesions accompanied with changes of fatty acid composition and eicosanoid production in ApoE knockout mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.259846 SP - jpet.119.259846 AU - Shuichi Takagahara AU - Hiromi Shinohara AU - Shigekazu Itokawa AU - Yoshinori Satomi AU - Ayumi Ando AU - Takeshi Yamamoto AU - Hideo Suzuki AU - Takuya Fujimoto AU - Kazuki Kubo AU - Shota Ikeda Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/09/05/jpet.119.259846.abstract N2 - Atherosclerosis is the major cause of cardiovascular (CV) events worldwide. Since inflammation plays a central role in atherosclerotic progression, targeting specific inflammatory pathways can be effective in preventing atherosclerosis and CV events. Delta-5 desaturase (D5D), encoded by fatty acid desaturase 1 (Fads1), is the rate-limiting enzyme for the conversion from dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA) in the ω-6 polyunsaturated fatty acid pathway. Several AA-derived eicosanoids (e.g., prostaglandins, thromboxanes, leukotrienes) are pro-inflammatory mediators, and promote atherosclerosis; however, most DGLA-derived eicosanoids have anti-inflammatory effects. To elucidate the effects of D5D inhibition on atherosclerosis, we generated a potent, orally available D5D inhibitor, compound-326, and examined its effects on Western-diet fed ApoE knockout (KO) mice. Oral administration of compound-326 (3-10 mg/kg/day) significantly inhibited the progression of atherosclerotic lesions in the aorta, significantly decreased AA levels while increased DGLA levels in the liver and blood accompanied with decreases in AA-derived eicosanoid production and increases in DGLA-derived eicosanoid production from the blood cells, and decreased inflammatory marker soluble ICAM-1 levels in plasma. We conclude that compound-326 prevented the progression of atherosclerosis in Western-diet fed ApoE KO mice via anti-inflammatory effects, suggesting that D5D inhibitors can be a novel remedy for preventing CV events.SIGNIFICANCE STATEMENT This study shows a D5D specific and orally available potent inhibitor provided the first evidence to support the concept that D5D inhibitors will be a novel remedy for preventing atherosclerosis and subsequent CV events through a novel anti-inflammatory mechanism. ER -