Omega-6 DPA and its 12-lipoxygenase-oxidized lipids regulate platelet reactivity in a nongenomic PPARα-dependent manner

被引：20

作者：

Yeung, Jennifer ^{[1
]}

Adili, Reheman ^{[1
]}

Yamaguchi, Adriana ^{[1
]}

Freedman, Cody J. ^{[2
]}

Chen, Angela ^{[1
]}

Shami, Ryan ^{[1
]}

Das, Aditi ^{[3
]}

Holman, Theodore R. ^{[2
]}

Holinstat, Michael ^{[1
,4
,5
]}

机构：

[1] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA

[2] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA

[3] Univ Illinois, Dept Mol Pharmacol & Toxicol, Urbana, IL USA

[4] Univ Michigan, Med Sch, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Med Sch, Dept Vasc Surg, Ann Arbor, MI 48109 USA

来源：

BLOOD ADVANCES | 2020年 / 4卷 / 18期

基金：

美国国家卫生研究院;

关键词：

FATTY-ACIDS; GAMMA; METABOLISM; THROMBOSIS; N-3; CYCLOOXYGENASE; EICOSANOIDS; SPECIFICITY; INHIBITION; OXYLIPINS;

D O I：

10.1182/bloodadvances.2020002493

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Arterial thrombosis is the underlying cause for a number of cardiovascular-related events. Although dietary supplementation that includes polyunsaturated fatty acids (PUFAs) has been proposed to elicit cardiovascular protection, a mechanism for antithrombotic protection has not been well established. The current study sought to investigate whether an omega-6 essential fatty acid, docosapentaenoic acid (DPA(n-6)), and its oxidized lipid metabolites (oxylipins) provide direct cardiovascular protection through inhibition of platelet reactivity. Human and mouse blood and isolated platelets were treated with DPA(n-6) and its 12-lipoxygenase (12-LOX)-derived oxylipins, 11-hydroxy-docosapentaenoic acid and 14-hydroxy-docosapentaenoic acid, to assess their ability to inhibit platelet activation. Pharmacological and genetic approaches were used to elucidate a role for DPA and its oxylipins in preventing platelet activation. DPA(n-6) was found to be significantly increased in platelets following fatty acid supplementation, and it potently inhibited platelet activation through its 12-LOX-derived oxylipins. The inhibitory effects were selectively reversed through inhibition of the nuclear receptor peroxisome proliferator activator receptor-alpha (PPAR alpha). PPAR alpha binding was confirmed using a PPARa transcription reporter assay, as well as PPAR alpha(-/-) mice. These approaches confirmed that selectivity of platelet inhibition was due to effects of DPA oxylipins acting through PPAR alpha. Mice administered DPAn-6 or its oxylipins exhibited reduced thrombus formation following vessel injury, which was prevented in PPAR alpha(-/-) mice. Hence, the current study demonstrates that DPA(n-6) and its oxylipins potently and effectively inhibit platelet activation and thrombosis following a vascular injury. Platelet function is regulated, in part, through an oxylipin-induced PPARa-dependent manner, suggesting that targeting PPARa may represent an alternative strategy to treat thrombotic-related diseases.

引用

页码：4522 / 4537

页数：16