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Studies on Vascular Inflammation and Skeletal Muscle Function Related to Atherosclerotic Diseases

長瀬, 裕樹 筑波大学 DOI:10.15068/0002008137

2023.09.04

概要

Delta-5 desaturase (D5D) is considered an attractive target molecule for treating
atherosclerosis [20, 21]. D5D is an enzyme mainly expressed in the liver [29, 30], which
metabolizes dihomo-γ-linolenic acid (DGLA) into arachidonic acid [31]. Arachidonic
acid is considered to play a role in the progression of atherosclerosis because of its proinflammatory properties [32]. Several reports have suggested that D5D gene
polymorphism in humans is associated with coronary artery diseases [33, 34]. D5Ddeficient apolipoprotein E (ApoE) knockout mice were resistant to diet-induced
development of atherosclerosis [20, 21]. A recent work discovered that an orally active
and selective D5D inhibitor, compound-326, that exhibited in vitro D5D inhibition (IC50:
22 nM) in human cells [35], reduced liver and blood arachidonic acid levels in mice,
accompanied by an increase in DGLA levels [21]. In ApoE knockout mice fed a Western
diet for 14 weeks, the atherosclerotic lesion area was significantly reduced by 15-week
treatment with compound-326 (1-week pre-treatment plus 14-week concurrent treatment
with Western diet). These results suggest that D5D inhibition could be a promising
strategy for the treatment of atherosclerosis.
Diet composition and duration are known to affect the characteristics of atherosclerotic
plaques [36]. ApoE knockout mice fed a Western diet for a long duration showed an
atherogenesis process strikingly similar to that seen in humans [37]; Paigen diet
(containing high cholesterol and cholate) induced severe dysfunction in the reverse
cholesterol transport system [38], resulting in high plasma cholesterol levels and
accelerated plaque development in ApoE knockout mice. These different diets are known
to induce different pathologies and states of inflammation [39, 40]. ...

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