Angelica Taylor Jameson

Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19 of 264 (∼7%) patients developed arterial thrombosis, including 4 of 41 (∼10%) patients with hypofibrinogenemia. However, 0 of 8 patients with fibrinogen αC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen αC region on arterial thrombosis, 2 mouse models were employed: (1) wild-type mice treated with lipid nanoparticles encapsulating small interfering RNA against fibrinogen (siFga) and (2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated αC region. Although siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the αC region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of αC-region–platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wild-type mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ1 administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen αC region promotes arterial thrombosis in hypofibrinogenemic conditions.

BACKGROUND: Obesity predisposes individuals to multiple pathologies, including metabolic dysfunction–associated steatotic liver disease and diabetes. Although it is known that accumulation of proinflammatory macrophages within adipose tissues drives adiposity and provokes obesity-linked sequelae, the molecular mechanisms that provoke macrophage dysfunction in obesity remain elusive. Macrophages express high levels of uPA (urokinase plasminogen activator), and uPA has been implicated in leukocyte migration. METHODS: Human adipose tissues from patients receiving bariatric surgery were collected and analyzed for uPA protein levels. To determine the impact of uPA in adipose tissue and subsequent high-fat diet (HFD)–induced weight gain and metabolic diseases, a novel mouse model with a conditional knockout of uPA ( Plau ^{fl /fl} ) was generated. Plau ^WT/WT , Plau ^KO/KO (global uPA deficiency), and Plau ^fl/fl /LysM Cre+ (conditional uPA deficiency in macrophages) mice were fed low-fat diet or HFD for up to 20 weeks. RESULTS: Protein levels of visceral adipose tissue uPA positively correlated with body mass index in patients with obesity, and uPA levels decreased in adipose tissue 2 years after bariatric surgery. The expression and activity of uPA also increased in the adipose tissue of HFD-fed control mice. Plau ^KO/KO mice displayed reduced weight gain and metabolic sequelae through 14 weeks on a HFD compared with Plau ^WT/WT mice, but not with prolonged HFD feeding. Interestingly, Plau ^fl/fl /LysM Cre+ mice developed HFD-induced metabolic pathologies equivalently to Plau ^WT/WT mice. CONCLUSIONS: Our findings suggest that global uPA deletion, but not selective deletion of uPA in LysM+ myeloid cells, attenuates the development of early-stage HFD-driven obesity and pathologies consistent with metabolic syndrome.