RT Journal Article
SR Electronic
T1 Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaam8475
DO 10.1126/scitranslmed.aam8475
VO 9
IS 417
A1 Shashar, Moshe
A1 Belghasem, Mostafa E.
A1 Matsuura, Shinobu
A1 Walker, Joshua
A1 Richards, Sean
A1 Alousi, Faisal
A1 Rijal, Keshab
A1 Kolachalama, Vijaya B.
A1 Balcells, Mercedes
A1 Odagi, Minami
A1 Nagasawa, Kazuo
A1 Henderson, Joel M.
A1 Gautam, Amitabh
A1 Rushmore, Richard
A1 Francis, Jean
A1 Kirchhofer, Daniel
A1 Kolandaivelu, Kumaran
A1 Sherr, David H.
A1 Edelman, Elazer R.
A1 Ravid, Katya
A1 Chitalia, Vipul C.
YR 2017
UL http://stm.sciencemag.org/content/9/417/eaam8475.abstract
AB Patients with chronic kidney disease can present a therapeutic conundrum because they are not only at increased risk of blood vessel thrombosis but also more likely to experience bleeding complications when treated with anticoagulants. Shashar et al. examined the mechanism of thrombosis in mouse models of renal disease and found a potential therapeutic target in a protein called STUB1. STUB1 is a ubiquitin ligase that interacts with tissue factor, a vascular wall protein that triggers the coagulation signaling cascade. The authors demonstrated that increase in STUB1 can prevent thrombosis but does not prolong bleeding in mouse models of kidney disease, suggesting that this may be a viable approach to antithrombotic management of patients.Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.