Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models

Abstract

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive interorgan and intercellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating proobesogenic and proinflammatory responses. Chronic inflammation further promotes insulin resistance and associated comorbidities. Obesity and type 2 diabetes are characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signalling via protease-activated receptors is intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled protease-activated receptor-2 signalling in the regulation of insulin resistance and metabolic inflammation in diet-induced obesity. Likewise, increases in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thromboinflammatory and cardiometabolic disorders.

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

“…Finally, severely ill COVID-19 patients are often associated with coagulopathy/thrombosis [193] and obesity as well as diabetes are characterized by a hypercoagulable state [194]. In obesity, this symptom is associated with the overexpression of multiple proteins associated to coagulation like thrombin, fibrinogen, coagulation factors (FXa, FVIIa, and FV), and activated protein C in diverse cell types including adipocytes, endothelial cells, and vascular smooth muscle cells [194]. This is even enhanced in patients with obesity and diabetes by acute hyperglycemia and hyperinsulinemia that were shown to trigger coagulation and fibrinolytic activity during inflammatory response [189].…”

“…Increased expression of eNOS, elevated production of ROS, activation of NF-ĸB, and chronic inflammation are some of the key factors for endothelial dysfunction with a shift to a vasoconstrictor, pro-thrombotic and chronic inflammatory state [ 171 , 192 ], likely fueling the severe impairment of COVID-19 on the cardiovascular system. Finally, severely ill COVID-19 patients are often associated with coagulopathy/thrombosis [ 193 ] and obesity as well as diabetes are characterized by a hypercoagulable state [ 194 ]. In obesity, this symptom is associated with the overexpression of multiple proteins associated to coagulation like thrombin, fibrinogen, coagulation factors (FXa, FVIIa, and FV), and activated protein C in diverse cell types including adipocytes, endothelial cells, and vascular smooth muscle cells [ 194 ].…”

Regulation of the Homeostatic Unfolded Protein Response in Diabetic Nephropathy

“…Thus, aPC inhibits hyperglycemia induced mitochondrial dysfunction in microvascular endothelial cells, and it protects against both endothelial and podocyte apoptosis in animal models of DN [73]. Multiple cell-specific receptor complexes mediate the protective functions of aPC [75]. On endothelial cells, the cytoprotective aPC signaling requires endothelial protein C receptor (EPCR) and protease activated receptor-1 (PAR1) [74,76].…”

Towards Goals to Refine Prophylactic and Therapeutic Strategies Against COVID-19 Linked to Aging and Metabolic Syndrome

“…Accordingly, dysfunctional shift of endothelial cells toward pro-thrombotic and pro-atherogenic states instigates severe impairment of COVID-19 on the cardiovascular system [51]. Diabetes, like obesity, is characterized by hypercoagulable state as well [114], featuring hypofibrinolysis and elevated levels of plasminogen activator inhibitor-1 (PAI-1) complement as well as increased platelet aggregation [115,116]. In patients with established T2DM, neutrophil extracellular traps (NETs), complexes of chromosomal DNA, histones, and granule proteins, were higher compared with healthy individuals [117,118].…”

“…Many severe COVID-19 patients show coagulation abnormalities with an increased risk of death, indicating the presence of a hypercoagulable state also detected in obesity and diabetes [114,254]. The coagulopathy associated with COVID-19 is a combination of low-grade DIC (mixture of thrombocytopenia, prolonged prothrombin time, and increased D-dimer) and confined pulmonary thrombotic microangiopathy, which can result in organ dysfunction in the most severely affected patients [254].…”