Pharmacological characterization of glyphlozins in isolated human platelets: in vitro, in vivo evaluation and molecular modeling

Abstract

Arterial Thrombosis and Atherosclerosis are among the leading causes of morbidity and mortality throughout the world, and their impact will increase even more in the coming decades, generating high costs for the health care system. Both events are regulated by complex interactions involving several families of molecules present in platelets. Platelets are responsible for homeostasis, for constructing new connective tissue and for revascularization. In this sense, it is important to shed light on both the molecular mechanisms and the in vitro and in vivo effects of gliflozins, given that the effects of these compounds on platelets and the cardiovascular system are still unclear due to the low availability of information. The main goal of this project, therefore, is to assess the molecular interactions and the in vitro and in vivo effects of empagliflozin, dapagliflozin and canagliflozin on platelet-rich plasma and washed human platelets. The preliminary results obtained by our group demonstrate that empagliflozin was capable of inhibiting platelet aggregation regarding the agonists collagen, ADP, thrombin and U46619, a stable analog of thromboxane A2. However, it is important to understand how and which pathways are responsible for the inhibition and the main biochemical mediators involved. To this end, we will use pharmacological tools as agonists and inhibitors for specific targets, in addition to immunohistochemical tests, in light of the relationship of several proteins involved in the process. In addition, we hope to use the results of the pharmacological characterization to apply molecular modeling tools to better understand these protein-ligand interactions. With this study, we hope to contribute with relevant information that will shed light on the action mechanisms of these molecules and enable a better or even a new approach for the treatment of Arterial Thrombosis and Atherosclerosis. (AU)