Abstract
Plasminogen (Plg) is a precursor of plasmin that degrades fibrin. A race-specific A620T mutation in Plg, also known as Plg-Tochigi, originally identified in a patient with recurrent venous thromboembolism, causes dysplasminogenemia with reduced plasmin activity. The Plg-A620T mutation is present in 3–4% of individuals in East Asian populations, and as many as 50,000 Japanese are estimated to be homozygous for the mutant 620T allele. In the present study, to understand the changes of thrombotic phenotypes in individuals with the mutant 620T allele, we generated knock-in mice carrying the homozygous Plg-A622T mutation (PlgT/T), an equivalent to the A620T mutation in human Plg. PlgT/T mice grew normally but showed severely reduced plasmin activity activated by urokinase, equivalent to ~8% of that in wild-type mice. In vitro fibrin clot lysis in plasma was significantly slower in PlgT/T mice than in wild-type mice. However, all experimental models of electrolytic deep vein thrombosis, tissue factor-induced pulmonary embolism, transient focal brain ischaemic stroke, or skin-wound healing showed largely similar phenotypes between PlgT/T mice and wild-type mice. Protein S-K196E mutation (Pros1E/E) is a race-specific genetic risk factor for venous thromboembolism. Coexistence in mice of PlgT/T and Pros1E/E did not affect pulmonary embolism symptoms, compared with those in Pros1E/E mice. Hence, the present study showed that the Plg-A622T mutation, which confers ~8% plasmin activity, does not increase the risk of thrombotic diseases in mice under experimental thrombotic conditions and does not modify the thrombotic phenotype observed in Pros1E/E mice. PlgT/T mice can be used to investigate the potential pathophysiological impact of the Plg-A620T mutation.
Highlights
Fibrinolysis is an intrinsic system for the decomposition of fibrin clots that is required to maintain vascular patency [1,2,3]
The plasma Plg antigen level in Plg-A622T mutation (PlgT/T) mice was reduced to approximately half (n = 10, 0.48 ± 0.23 U/ml) of that in wild-type mice (n = 10, 1.00 ± 0.50 U/ml) (Fig 2A), and the plasma plasmin activity after activation with urokinase-type Plg activator (uPA) was severely reduced in PlgT/T mice (n = 10, 8.1 ± 4.1%) compared to wild-type mice (n = 10, 100 ± 23.8%) (Fig 2B), though the Plg-A622T protein was converted to plasmin by the uPA treatment, as in wild-type Plg (Fig 2C)
Previous studies have shown that Plg-knockout mice developed multiple spontaneous thrombotic lesions in many tissues and exhibited a high level of ischaemic infarction when subjected to brain ischaemia injury [15, 16, 18]
Summary
Fibrinolysis is an intrinsic system for the decomposition of fibrin clots that is required to maintain vascular patency [1,2,3]. Hypoplasminogenemia is characterized by a reduced Plg activity and antigen level, and the common clinical manifestations among patients with severe hypoplasminogenemia are ligneous conjunctivitis and ligneous gingivitis [4, 5]. Dysplasminogenemia is characterized by reduced Plg activity with normal antigen limits. An amino acid substitution of Ala620 to Thr (Plg-A620T, rs121918027, c.1858G>A, Plg-A601T in the mature protein numbering, known as Plg-Tochigi), close to the active site His622 of the catalytic triad, was identified in patients with dysplasminogenemia [8, 9]. The Plg-A620T mutation, which is absent in white populations, appears with an allele frequency of 0.020 in Japanese [10], 0.015 in Chinese and 0.016 in Koreans [11]. The Japanese population is approximately 126 million. Extrapolating from these values, we estimate that approximately 1 of every 2,500 Japanese individuals is homozygous for the mutant allele, representing a total of as many as 50,000 individuals
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