Hemin-induced platelet activation is regulated by the ACKR3 chemokine surface receptor and has implications for passivation of vulnerable atherosclerotic plaques

被引：0

作者：

Laspa, Zoi ^{[1
]}

Dicenta-Baunach, Valerie ^{[1
]}

Schaale, David ^{[1
]}

Sigle, Manuel ^{[1
]}

Hochuli, Ravi ^{[1
]}

Castor, Tatsiana ^{[1
]}

Bayrak, Alp ^{[2
]}

Harm, Tobias ^{[1
]}

Mueller, Karin Anne Lydia ^{[1
]}

Pillaiyar, Thanigaimalai ^{[2
,3
]}

Laufer, Stefan ^{[2
,3
,4
]}

Rohlfing, Anne-Katrin ^{[1
]}

Gawaz, Meinrad Paul ^{[1
]}

机构：

[1] Univ Tubingen, Univ Hosp Tubingen, Dept Cardiol & Angiol, Tubingen, Germany

[2] Univ Tubingen, Inst Pharmaceut Sci, Dept Pharmaceut & Med Chem, Tubingen, Germany

[3] Tubingen Ctr Acad Drug Discovery & Dev TuCAD2, Tubingen, Germany

[4] Univ Tubingen, IFIT Cluster Excellence EXC 2180 Image Guided & Fu, Tubingen, Germany

来源：

FEBS JOURNAL | 2024年 / 291卷 / 24期

关键词：

ACKR3; hemin; intraplaque hemorrhage (IPH); multi-color flow cytometry; platelets; INTRAPLAQUE HEMORRHAGE; IRON; DISEASE; CXCR7; CYCLOPHILIN; PROGRESSION; THROMBUS;

D O I：

10.1111/febs.17294

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In vulnerable atherosclerotic plaques, intraplaque hemorrhages (IPH) result in hemolysis of red blood cells and release of hemoglobin and free hemin. Hemin activates platelets and leads to thrombosis. Agonism of the inhibitory platelet receptor ACKR3 inhibits hemin-dependent platelet activation and thrombus formation. To characterize the effect of hemin and ACKR3 agonism on isolated human platelets, multi-color flow cytometry and classical experimental setup such as light transmission aggregometry and a flow chamber assay were used. Hemin induces platelet aggregation and ex vivo platelet-dependent thrombus formation on immobilized collagen under a low shear rate of 500 s(-1), indicating that free hemin is a strong activator of platelet-dependent thrombosis. Recently, we described that ACKR3 is a prominent inhibitory receptor of platelet activation. Specific ACKR3 agonists but not conventional antiplatelet compounds such as COX-1 inhibitor (indometacin), ADP-receptor blocker (cangrelor), or PAR1 inhibitor (ML161) inhibit both hemin-dependent aggregation and thrombus formation. To further characterize the effect of hemin on platelet subpopulations, we established a multi-color flow cytometry assay. We found that hemin induces procoagulant (CD42b(pos)/PAC-1(neg)/AnnexinV(pos)), aggregatory (CD42b(pos)/PAC-1(pos)/AnnexinV(neg)), and inflammatory (CD42b(pos)/CXCR4(pos)/ACKR3(pos)/AnnexinV(pos)) platelet subpopulations. Treatment with ACKR3 agonists significantly decreased the formation of procoagulant and ACKR3(pos) platelets in response to hemin. We conclude that hemin is a strong activator for the formation of procoagulant platelets and thrombus formation which is dependent on the function of ACKR3. Activation of ACKR3 using specific agonists may offer a therapeutic strategy to regulate the vulnerability of atherosclerotic plaques in areas of IPH.

引用

页码：5420 / 5434

页数：15