EMILIN2 regulates platelet activation, thrombus formation, and clot retraction

• Published in: PloS one Vol. 10; no. 2; p. e0115284
• Main Authors: Huang, Menggui, Sannaningaiah, Devaraja, Zhao, Nan, Gong, Yanqing, Grondolsky, Jessica, Hoover-Plow, Jane
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.02.2015; Public Library of Science (PLoS)
• Subjects: Adenosine; Adenosine diphosphate; Agglomeration; Animal models; Animal tissues; Animals; ATPases; Blood clots; Blood Coagulation; Blood plasma; Blood platelets; Blood Platelets - metabolism; Blood Platelets - pathology; Cardiology; Cardiovascular diseases; Cerebral blood flow; Chromosome 18; Chromosome deletion; Chromosomes; Clonal deletion; Clotting; Collagen; Coronary artery disease; Elastin; Elastin microfibril interface located protein; Genomes; Glycoproteins - genetics; Glycoproteins - metabolism; Heart diseases; Heart failure; Humans; Ischemia; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Knockout; Occlusion; Platelet Aggregation; Platelets; Proteins; Quantitative genetics; Quantitative trait loci; Risk factors; Rodents; Signal Transduction - physiology; Stem cell transplantation; Stem cells; Thrombin; Thromboembolism; Thrombosis; Thrombosis - genetics; Thrombosis - metabolism; Thrombosis - pathology; Cleveland Ohio; Ohio; United States > US; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115284

Thrombosis, like other cardiovascular diseases, has a strong genetic component, with largely unknown determinants. EMILIN2, Elastin Microfibril Interface Located Protein2, was identified as a candidate gene for thrombosis in mouse and human quantitative trait loci studies. EMILIN2 is expressed during cardiovascular development, on cardiac stem cells, and in heart tissue in animal models of heart disease. In humans, the EMILIN2 gene is located on the short arm of Chromosome 18, and patients with partial and complete deletion of this chromosome region have cardiac malformations. To understand the basis for the thrombotic risk associated with EMILIN2, EMILIN2 deficient mice were generated. The findings of this study indicate that EMILIN2 influences platelet aggregation induced by adenosine diphosphate, collagen, and thrombin with both EMILIN2-deficient platelets and EMILIN2-deficient plasma contributing to the impaired aggregation response. Purified EMILIN2 added to platelets accelerated platelet aggregation and reduced clotting time when added to EMILIN2-deficient mouse and human plasma. Carotid occlusion time was 2-fold longer in mice with platelet-specific EMILIN2 deficiency, but stability of the clot was reduced in mice with both global EMILIN2 deficiency and with platelet-specific EMILIN2 deficiency. In vitro clot retraction was markedly decreased in EMILIN2 deficient mice, indicating that platelet outside-in signaling was dependent on EMILIN2. EMILIN1 deficient mice and EMILIN2:EMILIN1 double deficient mice had suppressed platelet aggregation and delayed clot retraction similar to EMILIN2 mice, but EMILIN2 and EMILIN1 had opposing affects on clot retraction, suggesting that EMILIN1 may attenuate the effects of EMILIN2 on platelet aggregation and thrombosis. In conclusion, these studies identify multiple influences of EMILIN2 in pathophysiology and suggest that its role as a prothrombotic risk factor may arise from its effects on platelet aggregation and platelet mediated clot retraction.