Objective Aortic valve stenosis (AS) is characterized by fibrosis and calcification of valves leading to aortic valve (AV) narrowing, resulting in high wall shear stress (WSS) across the valves. We previously demonstrated that high shear stress can activate platelet-derived transforming growth factor-β1 (TGF-β1), a cytokine implicated inducing fibrosis and calcification. The aim of this study was to invest the role of shear-induced platelet release of TGF-β1 and its activation in AS. Approach and Results We studied hypercholesterolemic Ldlr−/−Apob100/100/Mttpfl/fl/Mx1Cre+/+ (Reversa) mice that develop AS on western diet (WD) and a surgical ascending aortic constriction (AAC) mouse model that acutely simulates the hemodynamics of AS to study shear-induced platelet TGF-β1 release and activation. Reversa mice on WD for 6 months had thickening of the AVs, increased WSS and increased plasma TGF-β1 levels. There were weak and moderate correlations between WSS and TGF-β1 levels in the progression and reversed Reversa groups, and a stronger correlation in the AAC model in WT mice, but not in mice with a targeted deletion of megakaryocyte and platelet TGF-β1 (Tgfb1flox). Plasma total TGF-β1 levels correlated with collagen deposition in the stenotic valves in Reversa mice. Although active TGF-β1 levels were too low to be measured directly, we found: 1. canonical TGF-β1 (p-Smad2/3) signaling in the leukocytes and canonical and non-canonical (p-Erk1/2) TGF-β1 signaling in AVs of Reversa mice on a WD, and 2. TGF-β1 signaling of both pathways in the AAC stenotic area in WT, but not Tgfb1flox mice. Conclusions Shear-induced, platelet-derived TGF-β1 activation may contribute to AS.
Objective Treatment of myocardial infarction (MI) within the first 1–2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbβ3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly (IM) by autoinjector to facilitate its use in the pre-hospital setting. Here we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models. Approach and Results RUC-4 was ~20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60–80 mg/ml). It shared RUC-2’s specificity for αIIbβ3 vs αVβ3, did not prime the receptor to bind fibrinogen, or induce changes in β3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl3-induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human, but not mouse platelets. IM injection of RUC-4 in non-human primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5–24 hours. Conclusions RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a pre-hospital therapy of MI, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.