The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Sowmya Shivanna, Kumaran Kolandaivelu, Moshe Shashar, Mostafa Belghasim, Laith Al-Rabadi, Mercedes Balcells, Anqi Zhang, Janice Weinberg, Jean Francis, Michael P. Pollastri, Elazer R. Edelman, David H. Sherr, Vipul C. Chitalia

Producció científica: Article en revista indexadaArticleAvaluat per experts

89 Cites (Scopus)

Resum

Patients withCKDsuffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precisemechanismand treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targetingAHRenhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in amanner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncoveredAHRas an antithrombotic target andAHRantagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.

Idioma originalAnglès
Pàgines (de-a)189-201
Nombre de pàgines13
RevistaJournal of the American Society of Nephrology
Volum27
Número1
DOIs
Estat de la publicacióPublicada - de gen. 2016

Fingerprint

Navegar pels temes de recerca de 'The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia'. Junts formen un fingerprint únic.

Com citar-ho