High Fat Diet Exacerbates Uridine Adenosine Tetraphosphate (Up4A)-Mediated Decrease in Coronary Flow in Atherosclerotic ApoE Knockout Mice: Role of Purinergic P2X1 Receptors

Introduction: Up4A, a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorder via activation of P2 receptors (P2R). Here, we evaluated the vasoactive effect of Up4A on coronary flow (CF) in ApoE knockout mice (KO) with and without high fat diet (HFD). Methods: Functional studies were conducted in isolated mouse hearts using Langendorff and isolated coronary arteries (diameter≈100 μm) using wire Myograph. Immunofluorescence was performed for P2X1R expression in isolated coronary arteries. Results: There was no significant difference in baseline CF (ml/min/g) among wild type (WT, 18.4±0.5), ApoE KO (17.6±1.1) and ApoE KO+HFD (15.9±1.0). Infusion of Up4A (10-9-10-5 M) resulted in a dose-dependent reduction in CF in WT (by ~38%), which was similar to ApoE KO (by ~40%). In isolated coronary arteries of WT, Up4A produced a mild contraction up to ~20%, indicating a vasoconstrictor effect of Up4A. Notably, Up4A further decreased CF in ApoE+HFD as compared to ApoE. Moreove...