kcc-009 and Vascular-Calcification

Arterial calcification (AC) is a hallmark of many serious diseases, including atherosclerosis, chronic kidney disease, and diabetes. AC may also develop as a side-effect of therapy with anticoagulants, such as warfarin which is widely used for prophylaxis of thrombosis. In our studies, we established the relation between warfarin-induced AC and activation of enzyme transglutaminase 2 (TG2) and β-catenin signaling. We showed that TG2-specific inhibitor KCC-009 significantly attenuated the damaging effects of warfarin on arterial tissue. A similar protective effect was also achieved with a dietary bioflavonoid quercetin that inhibits TG2 and β-catenin signaling. We have shown that quercetin intercepts the chondrogenic transformation of vascular smooth muscle and also drastically attenuates calcifying cartilaginous metaplasia in another model of AC caused by genetic loss of matrix gla protein (MGP). These findings suggest that quercetin may be considered as a promising anti-AC therapeutic in the clinical settings of warfarin supplementation and MGP dysfunction. Further studies are required to test the efficacy of quercetin on other types of AC.

Topics: Animals; beta Catenin; Enzyme Inhibitors; Humans; Isoxazoles; Signal Transduction; Transglutaminases; Vascular Calcification

In vitro, transglutaminase-2 (TG2)-mediated activation of the β-catenin signaling pathway is central in warfarin-induced calcification, warranting inquiry into the importance of this signaling axis as a target for preventive therapy of vascular calcification in vivo.. The adverse effects of warfarin-induced elastocalcinosis in a rat model include calcification of the aortic media, loss of the cellular component in the vessel wall, and isolated systolic hypertension, associated with accumulation and activation of TG2 and activation of β-catenin signaling. These effects of warfarin can be completely reversed by intraperitoneal administration of the TG2-specific inhibitor KCC-009 or dietary supplementation with the bioflavonoid quercetin, known to inhibit β-catenin signaling. Our study also uncovers a previously uncharacterized ability of quercetin to inhibit TG2. Quercetin reversed the warfarin-induced increase in systolic pressure, underlying the functional consequence of this treatment. Molecular analysis shows that quercetin diet stabilizes the phenotype of smooth muscle and prevents its transformation into osteoblastic cells.. Inhibition of the TG2/β-catenin signaling axis seems to prevent warfarin-induced elastocalcinosis and to control isolated systolic hypertension.

Topics: Animals; Aorta; Aortic Diseases; beta Catenin; Blood Pressure; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; GTP-Binding Proteins; Isoxazoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Osteogenesis; Phosphorylation; Protein Glutamine gamma Glutamyltransferase 2; Quercetin; Rats; Rats, Wistar; Signal Transduction; Transglutaminases; Vascular Calcification; Warfarin