Prothrombotic effects of high uric acid in mice via activation of MEF2C-dependent NF-κB pathway by upregulating let-7c

Abstract

Serum uric acid is reportedly associated with thrombosis development. However, still unclear is the mechanism of high uric acid in thrombosis with the involvement of let-7c. In an aim to fill this void, we conducted this study by treating mice and human umbilical vein endothelial cells with high uric acid. Analysis indicated that let-7c was upregulated in hyperuricemia patients as well as in mice and human umbilical vein endothelial cells treated with high uric acid. Furthermore, high uric acid inhibited myocyte enhancer factor-2C, but activated nuclear factor-kappa B pathway in human umbilical vein endothelial cells. Then the targeting relationship between let-7c and myocyte enhancer factor-2C was verified. On the one hand, high uric acid shortened activated partial thromboplastin time and prothrombin time of mice and declined tissue plasminogen activator level. Additionally, the treatment prolonged thrombin time and elevated the levels of thrombosis related molecules or proteins such as Fibrinogen and D-dimer. Nevertheless, these alternations could be reversed by inhibition of let-7c and nuclear factor-kappa B pathway or overexpressing myocyte enhancer factor-2C. To sum up, our results uncovered the pro-thrombotic effect of high uric acid in mice by activating myocyte enhancer factor-2C-dependent nuclear factor-kappa B pathway via let-7c upregulation.

The association between hyperuricemia and cardiovascular disease history: A cross-sectional study using KoGES HEXA data

“…In a recent animal study, increased uric acid levels activated the myocyte enhancer factor-2C-dependent and nuclear factor-κB pathways by let-7c and generating thrombosis. [ 40 ]…”

“…In a recent animal study, increased uric acid levels activated the myocyte enhancer factor-2C-dependent and nuclear factor-κB pathways by let-7c and generating thrombosis. [40] Despite the large population database, this study had several limitations. First, data from the KoGES did not have all the records regarding potential confounders, including treatment of hyperuricemia, duration of disease, drug intake, and coronary angiography procedure; as such, the results should be interpreted with caution.…”

Hyperuricemia: A key contributor to endothelial dysfunction in cardiovascular diseases

“…Cimmino et al 90 reported that UA at high levels enhanced the procoagulant function of tissue factor (TF) and decreased the expression of its physiological inhibitor TFPI in HUVECs, leading to the acquisition of a prothrombotic phenotype. Similarly, a shorten activated partial thromboplastin time (APTT) and prothrombin time (PT), a prolonged thrombin time (TT), and increased levels of fibrinogen and D‐dimer have been observed in the serum of a HUA mouse model 91 . These effects may have been partially due to myocyte enhancer factor 2C (MEF2C)‐dependent nuclear factor kappa B (NF‐κB) activation in ECs, which is regulated by let‐7c and results in significant increases in the protein levels of plasminogen activator inhibitor 1 (PAI‐1) and TF but marked reductions in tissue plasminogen activator (t‐PA) expression 91 .…”

“…Similarly, a shorten activated partial thromboplastin time (APTT) and prothrombin time (PT), a prolonged thrombin time (TT), and increased levels of fibrinogen and D-dimer have been observed in the serum of a HUA mouse model. 91 These effects may have been partially due to myocyte enhancer factor 2C (MEF2C)-dependent nuclear factor kappa B (NF-κB) activation in ECs, which is regulated by let-7c and results in significant increases in the protein levels of plasminogen activator inhibitor 1 (PAI-1) and TF but marked reductions in tissue plasminogen activator (t-PA) expression. 91 In addition, endothelial microparticles (MPs) participate in the mechanism underlying HUA-induced coagulation.…”

Uric Acid—An Emergent Risk Marker for Thrombosis?

“…Moreover, let 7-c is interconnected with platelets functionality. In a study performed on an animal model of hyperuricemia, increased levels of SUA generated thrombosis through the activation of MEF2C-dependent and NF-ƙB pathways by let 7-c [ 23 ]. In mice, the inhibition of xanthine oxidase by febuxostat led to a decrease in the expression of PAI-1 and TF, thus diminishing the prothrombotic state [ 24 ].…”