Decreased fibrinolytic activity is strongly associated with cardiovascular disease. Plasminogen activator inhibitor-1, (PAI-1, Serpine1) is a major circulating fibrinolysis inhibitor, >80% of which is found in platelets. Platelet PAI-1 (pPAI-1) is produced by the megakaryocytes and packaged directly into platelets, thus it is distinct from plasma PAI-1. Plasma PAI-1 levels have been extensively studied and consistently linked with cardiovascular disease. However, variation in pPAI-1, either in the presence or absence of cardiovascular disease, is unknown. To study PAI-1 expression, we surveyed ten mouse strains for pPAI-1 antigen. In particular, the LEWES/EiJ mouse strain had significantly increased pPAI-1 (and Serpine1 mRNA), with an average concentration of 3.1 pg/μg total platelet protein compared to C57BL/6J (B6), which had an average pPAI-1 concentration of 0.4 pg/μg total protein (q=0.0018). Outcrossing LEWES/EiJ x C57BL/6J produced F1 mice with average pPAI-1 levels of 1.6 pg/μg total protein (q=0.0018), suggesting a semidominantly-inherited Serpine1 regulatory effect. To identify pPAI-1 regulatory regions, we produced 48 F2 mice, measured pPAI-1 levels and genotyped 12 (with <0.4 pg/μg total protein) and 12 (with >1.0 pg/μg total protein) using the Mouse Universal Genotyping Array (MegaMUGA). QTL analysis revealed several candidate regions including a major significant 14.4 megabase locus (128.2-142.6 megabases) on Chromosome 5 (LOD score = 4.81). The Serpine1 gene resides within this candidate interval, strongly suggesting that a Serpine1 cis-eQTL is responsible for pPAI-1 expression differences between LEWES/EiJ and C57BL/6J. Identifying pPAI-1 expression control elements offers insights into platelet-specific gene expression and identifies a putative therapeutic target for modulating hemostasis.
Low Molecular Weight Antagonists of Plasminogen Activator Inhibitor-1: Therapeutic Potential in Cardiovascular Disease