ANXA7 Regulates Platelet Lipid Metabolism and Ca2+ Release in Arterial Thrombosis

被引：19

作者：

Manke, Mailin-Christin ^{[1
]}

Geue, Sascha ^{[1
]}

Coman, Cristina ^{[4
]}

Peng, Bing ^{[5
,6
]}

Kollotzek, Ferdinand ^{[1
]}

Muenzer, Patrick ^{[1
]}

Walker, Britta ^{[1
]}

Huber, Stephan M. ^{[2
]}

Rath, Dominik ^{[1
]}

Sickmann, Albert ^{[6
]}

Stegner, David ^{[7
,8
]}

Duerschmied, Daniel ^{[9
]}

Lang, Florian ^{[3
]}

Nieswandt, Bernhard ^{[7
,8
]}

Gawaz, Meinrad ^{[1
]}

Ahrends, Robert ^{[4
,6
]}

Borst, Oliver ^{[1
]}

机构：

[1] Univ Tubingen, Dept Cardiol Angiol & Cardiovasc Med, Tubingen, Germany

[2] Univ Tubingen, Dept Radiat Oncol, Tubingen, Germany

[3] Univ Tubingen, Dept Physiol, Tubingen, Germany

[4] Univ Vienna, Dept Analyt Chem, DEG Heisenberg Grp Thrombocardiol, Vienna, Austria

[5] Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden

[6] Leibniz Inst Analyt Wissensch ISAS, Dortmund, Germany

[7] Univ Wurzburg, Univ Hosp, Inst Expt Biomed, Wurzburg, Germany

[8] Univ Wurzburg, Rudolf Virchow Ctr Integrat & Translat Bioimaging, Wurzburg, Germany

[9] Univ Freiburg, Fac Med, Heart Ctr, Freiburg, Germany

来源：

CIRCULATION RESEARCH | 2021年 / 129卷 / 04期

关键词：

annexin A7; calcium signaling; lipids; lipoxygenase; oxylipins; platelet activation; thrombosis; ANNEXIN-VII SYNEXIN; GLYCOPROTEIN-VI; A7; 12-LIPOXYGENASE; ACTIVATION; EXPRESSION; CALCIUM; INVOLVEMENT; ADHESION; PLAYS;

D O I：

10.1161/CIRCRESAHA.121.319207

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rationale: Platelet activation after contact to subendothelial collagen leads to acute arterial thrombosis. ANXA7 (Annexin A7) is a phospholipid-binding protein participating in the regulation of intracellular Ca2+ and exocytosis. Objective: The present study aimed to determine the role of ANXA7 in platelet Ca2+ signaling and lipid metabolism during platelet activation in arterial thrombosis using the ANXA7 inhibitor 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine (ABO) and gene-targeted mice lacking Anxa7 (Anxa7(-/-)). Methods and Results: ANXA7 is strongly expressed in platelets. Functionally, luminescence aggregometry revealed significantly abrogated aggregation and secretion of ABO-treated or Anxa7(-/-) platelets when compared with untreated or Anxa7(+/+) platelets after activation with collagen or the GPVI (glycoprotein VI)-specific agonist collagen-related peptide. Furthermore, while both thrombus formation on collagen-coated surfaces under high arterial shear rates in ABO-treated or Anxa7-deficient whole blood, and thrombotic vascular occlusion after FeCl3-induced injury in vivo in Anxa7(-/-) bone marrow chimeric mice were significantly diminished, no prolongation of bleeding time was observed in ABO-treated or Anxa7(-/-) mice. Fura-2-AM spectrofluorimetry unraveled a blunted [Ca2+](i) increase in ABO-treated or Anxa7(-/-) platelets after GPVI stimulation. Due to an abolished phospholipase C gamma 2 phosphorylation, Anxa7(-/-) platelets displayed abrogated intracellular Ca2+ mobilization following collagen-related peptide-dependent platelet activation. Quantitative lipidomics analysis further revealed that ANXA7 critically affects platelet oxylipin metabolism following GPVI-dependent platelet activation. Anxa7(-/-) platelets showed a significantly reduced generation of several bioactive metabolites, particularly thromboxane A(2) and 12(S)-hydroxy-eicosatetraenoic acid. Finally, defective phospholipase C gamma 2 phosphorylation and blunted [Ca2+](i) increase in Anxa7(-/-) platelets could be rescued by exogenous addition of 12(S)-hydroxy-eicosatetraenoic acid, indicating that ANXA7 is a critical regulator of the platelet 12-lipoxygenase in GPVI-dependent platelet Ca2+ signaling during arterial thrombosis. Conclusions: The present study unravels ANXA7 as a regulator of oxylipin metabolism and Ca2+-dependent platelet activation downstream of GPVI. ANXA7 plays an important role in platelet signaling during arterial thrombosis and thus may reflect a promising target for novel antiplatelet strategies.

引用

页码：494 / 507

页数：14

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