The role of TPA in reducing LP(a) assembly - epidemiological, genome-wide association, and mendelian randomization studies have demonstrated that lipoprotein (a) is an independent causal risk factor…

The National Heart, Lung, and Blood Institute awarded The Medical College of Wisconsin, Inc., $812,747 on July 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct epidemiological, genome-wide association, and Mendelian randomization studies on the role of tissue-type plasminogen activator (tPA) in reducing lipoprotein(a) [Lp(a)] assembly.

The research addresses how tPA, a serine protease that initiates fibrinolysis by converting plasminogen to plasmin, may regulate plasma Lp(a) levels through mechanisms beyond genetic control. Lp(a) is an independent causal risk factor for cardiovascular disease, associated with up to eight times higher risk of myocardial infarction and ischemic stroke. The project will investigate hepatocyte synthesis of tPA, its contribution to circulating tPA concentration, and observations from severe COVID-19 patients showing inverse changes in tPA activity and Lp(a) levels during hospitalization and recovery.

Performance occurs in Wauwatosa, Wisconsin, with a completion date of March 31, 2030. Versiti Blood Health, Inc. (Versiti Wisconsin Inc.), a non-profit transfusion medicine and hematology research organization, receives a sub-award effective August 6, 2026, to support the role of tPA in reducing Lp(a) assembly research activities.

The role of TPA in reducing LP(a) assembly - epidemiological, genome-wide association, and mendelian randomization studies have demonstrated that lipoprotein (a) is an independent causal risk factor for cardiovascular disease. High LP(a) levels are associated with up to 8 times higher risk of myocardial infarction and ischemic stroke, which are thrombotic events that can occur in atherosclerotic vessels. LP(a) consists of two main protein components that may both contribute to atherosclerosis and thrombosis: a full-length apolipoprotein B100 (APOB) moiety and an apolipoprotein (a) [APO(a)] moiety. The APOB moiety is pro-atherogenic because IT is a low-density lipoprotein (LDL)-like particle with a scaffolding protein APOB. The APO(a) moiety is pro-thrombotic because IT is a structural homolog to plasminogen and inhibits plasminogen activation which is the primary mechanism breaking down blood clots, a process called fibrinolysis. The plasma level of LP(a) was thought to be mostly determined by the genetic variants of LPA gene, and therefore, its level theoretically should be stable, leading to the numerous clinical recommendations for measuring LP(a) once in lifetime. However, recent evidence shows changes in LP(a) levels in the same individual. These changes highlight the presence of regulatory mechanisms, beyond genetics, that regulate plasma LP(a) levels. Fibrinolysis is initiated by a serine protease tissue-type plasminogen activator (TPA) by converting plasminogen to its active form, plasmin, which cleaves cross-linked fibrin clots. Recently we have made several observations that suggest a potential role of TPA in lowering LP(a) levels. We have shown that: 1) hepatocytes synthesize TPA and hepatocyte-derived TPA contributes to circulating TPA concentration and fibrinolysis. 2) in patients with severe covid-19, TPA activity decreases while LP(a) increasing during hospitalization. Among those who survived, LP(a) decreased and TPA enzymatic activity increased after recovering from covid-19 symptoms. 3) the kringle 2 domain of TPA directly binds APOB's the N-terminus, where the kringle IV types 5-8 domains of APO(a) also interacts with, suggesting a potential role of TPA in competing with APO(a) for its interaction with APOB. Our new preliminary data showed that 1) TPA forms complexes with APOB's N-terminal fragments APOB9, APOB15, or APOB18 where APO(a) interacts with APOB through lysine-mediated mechanisms. 2) a lysine analog, tranexamic acid, partially blocks the interaction between TPA and APOB. 3) silencing TPA in human primary hepatocytes increased LP(a) in serum-free culture medium. 4) silencing PAI1 in human primary hepatocytes increases LP(a) levels. Based on these compelling data, in this proposal, we will test the central hypothesis that TPA inhibits LP(a) assembly by blocking APOB binding to APO(a) using LP(a) transgenic mice, human primary hepatocytes and human plasma samples in the following specific aims: aim 1. To test the hypothesis that TPA blocks APOB-APO(a) interaction. Aim 2. To test the hypothesis that TPA reduces the available APOB and APO(a). Aim 3. To test the hypothesis that reducing LP(a) by increasing hepatocyte TPA lowers atherosclerosis and improves fibrinolysis.