Role of the proteoglycan, serglycin, in platelet exocytosis

Abstract

Platelet granule secretion is essential for the maintenance of the vascular system and influences cardiovascular diseases such as stroke and myocardial infarction. Platelets secrete their granules in response to vascular damage, which promotes clot formation; but, excessive secretion can lead to occlusive thrombosis. Platelets are derived from large progenitor cells called megakaryocytes that reside in the bone marrow. These cells project proplatelet extensions into circulation for platelet production. Platelet secretory granules are synthesized within megakaryocytes and packaged into proplatelets. Serglycin is an intra‐granular, chondroitin sulfate proteoglycan produced by several hematopoietic cells. Serglycin−/− mice exhibit decreased agonist‐dependent secretion of α‐granule cargo (Platelet Factor‐4 (PF4), MIP‐1) despite showing normal exposure of α‐granule membrane protein (P‐selectin), suggesting a defect in granule cargo storage and/or solubility. We hypothesize that the negative charges present on serglycin are vital for the retention and solubility of α‐granule cargo during their synthesis in megakaryocytes and packaging into platelet granules. We examined primary megakaryocytes isolated from bone marrow of wild‐type and serglycin−/− mice. Serglycin−/− megakaryocytes showed an increase in PF4 in the culture media, coupled with a decrease in PF4 associated with cell pellets, as measured by ELISA assays. Fluorescent microscopy also showed a decrease in the retention of fibrinogen, a soluble factor endocytosed by megakaryocytes and sorted into α‐granules, in serglycin−/− megakaryocytes. Additionally, myelofibrosis and splenomegaly were observed in serglycin−/− mice. These studies contribute to an understanding of the physiological function of serglycin in megakaryocytes and to the mechanism of α‐granule biosynthesis.Support or Funding InformationSupported by HL56652, HL138179 and VA Merit AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.