EMILIN2 Regulates Platelet Activation, Thrombus Formation, and Clot Retraction

Abstract

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.

Abdominal Aortic Aneurysms Growth Is Associated With High Concentrations of Plasma Proteins in the Intraluminal Thrombus and Diseased Arterial Tissue

“…29 and which is associated with the formation of elastic fibers. In line with this, patients with thoracic dissections had downregulated EMILIN-1, 30 possibly indicating that EMILIN-1 is important for intact elastic tissue.…”

Proteomic Profiling of Hematopoietic Stem/Progenitor Cells after a Whole Body Exposure of CBA/CaJ Mice to Titanium (48Ti) Ions

“…It is also known that EMILIN2 is a binding partner of EMILIN1 [46]. Recently, it has been found that EMILIN2 regulates platelet activation, thrombus formation and clot retraction [47]. Hence, deficiency or reduction in EMILIN2 would impair platelet aggregation response.…”

Emilin 2 promotes the mechanical gradient of the cochlear basilar membrane and resolution of frequencies in sound

“…Measurement of the auditory-evoked brainstem response, an indicator of overall auditory function, showed moderately elevated thresholds in Emilin2 −/− mice compared to +/+ mice for a click stimulus and a range of specific frequencies (8,16, and 32 kHz; fig. S3, B and C).…”

“…Emilin 1 and emilin 2 can associate with microfibrils in skin extracts (13), and Emilin1-deficient mice display narrowing of blood vessels and hypertension (14). Emilin 2 has been reported to influence angiogenesis (15) and thrombosis (16), but its wider roles are unknown. The prominent expression of emilin 2 in the cochlea compared to other tissues (12) led us to investigate a specific role in frequency resolution.…”