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

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.