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.
Highlights
EMILIN2 (E2) is a 116 kD extracellular matrix glycoprotein [1,2] with five protein domains: Cterminal C1q domain, proline-rich domain, collagenous domain, coiled-coil domain, and Nterminal cysteine-rich domain (EMI domain)
The Pf4-Cre recombinant mice were crossed with E2flox/flox to generate the E2 platelet deficient mice (E2p-/-) that are compared to wild-type mice with Pf4-cre (WTp)
Mice were genotyped by PCR (Fig. 1B), and we confirmed by qRT-PCR that there was no E2 mRNA detected in the E2-/- mice (Fig. 1C)
Summary
EMILIN2 (E2) is a 116 kD extracellular matrix glycoprotein [1,2] with five protein domains: Cterminal C1q domain, proline-rich domain, collagenous domain, coiled-coil domain, and Nterminal cysteine-rich domain (EMI domain). E2 was first identified as a binding partner to EMILIN1 (E1) and both are elastin microfibril interface proteins [1]. Microfibrils consisting of a fibrillin scaffold, elastin, and other proteins, including the EMILINs, are assembled outside the cell to form elastic fibers that impart the elasticity to tissue and vessels. Fibulins, fibrillar proteins, and thrombospondins are all microfibril constituents and are all required for recovery from injury and prevention of vascular disease [5]. Other elastin/microfibril proteins, namely fibulin-1 [6,7], multimerin-1 (MMNR1) [8], and microfibril-associated glycoprotein 1(MAGP1) [9], function in hemostasis and thrombosis
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