Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.
German Center of Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany.
Blood. 2021 Mar 25;137(12):1641-1651. doi: 10.1182/blood.2020009405.
Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression is regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/- mice did not present detectable mature SMOC1 protein. Platelets from SMOC1+/- mice demonstrated attenuated responsiveness to thrombin (platelet neutrophil aggregate formation, aggregation, clot formation, Ca2+ increase, and β3 integrin phosphorylation), whereas responses to other platelet agonists were unaffected. SMOC1 has been implicated in transforming growth factor-β signaling, but no link to this pathway was detected in platelets. Rather, the SMOC1 Kazal domain directly bound thrombin to potentiate its activity in vitro, as well as its actions on isolated platelets. The latter effects were prevented by monoclonal antibodies against SMOC1. Platelets from miR-223-deficient mice expressed high levels of SMOC1 and exhibited hyperreactivity to thrombin that was also reversed by preincubation with monoclonal antibodies against SMOC1. Similarly, SMOC1 levels were markedly upregulated in platelets from individuals with type 2 diabetes, and the SMOC1 antibody abrogated platelet hyperresponsiveness to thrombin. Taken together, we have identified SMOC1 as a novel thrombin-activating protein that makes a significant contribution to the pathophysiological changes in platelet function associated with type 2 diabetes. Thus, strategies that target SMOC1 or its interaction with thrombin may be attractive therapeutic approaches to normalize platelet function in diabetes.
分泌型钙结合模块蛋白 1（SMOC1）是骨粘连蛋白/富含半胱氨酸的酸性分泌蛋白相关细胞外基质蛋白，其表达受 microRNA-223（miR-223）调控。由于血小板富含 miR-223，因此本研究调查了 SMOC1 的表达及其对血小板功能的贡献。人源和鼠源血小板均表达 SMOC1，而 SMOC1+/- 小鼠的血小板则未检测到成熟 SMOC1 蛋白。SMOC1+/- 小鼠的血小板对凝血酶的反应性减弱（血小板-中性粒细胞聚集形成、聚集、凝块形成、Ca2+增加和β3 整合素磷酸化），而对其他血小板激动剂的反应不受影响。SMOC1 已被牵连到转化生长因子-β信号通路中，但在血小板中未检测到与该通路的联系。相反，SMOC1 的 Kazal 结构域直接与凝血酶结合，增强其体外活性，以及对分离血小板的作用。这些作用可被针对 SMOC1 的单克隆抗体所阻断。miR-223 缺陷型小鼠的血小板表达高水平的 SMOC1，对凝血酶表现出超反应性，这种超反应性也可被针对 SMOC1 的单克隆抗体预先孵育所逆转。同样，2 型糖尿病患者的血小板中 SMOC1 水平显著上调，并且 SMOC1 抗体可消除血小板对凝血酶的高反应性。总之，我们已确定 SMOC1 为一种新型的凝血酶激活蛋白，其对与 2 型糖尿病相关的血小板功能的病理生理变化做出了重要贡献。因此，针对 SMOC1 或其与凝血酶相互作用的策略可能是一种有吸引力的治疗方法，可使糖尿病患者的血小板功能正常化。
