Characterization of Adenosine A2A receptors expression in hypercholesterolemia to understand the cardiovascular risk

Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity worldwide. Hypercholesterolemia [elevated blood levels of total- and low-density lipoprotein-cholesterol (T-C and LDL-C)] is one of the main CVD risk factors and hypocholesterolemic treatments (statins, PCSK9 inhibitors, LDL-apheresis) are part of the daily patient care. During ischemia, hypoxia and inflammation, adenosine blood concentration increases and activates A2A adenosine receptors (A2AR, expressed by endothelial cells and lymphocytes), thus producing a protective effect via its vasodilatory and immunosuppressive functions. Alterations of A2A receptors expression and properties have been found in CVD patients. In a previous pilot study, we described a lower A2AR expression in peripheral blood mononuclear cells (PBMCs) of a small cohort of patients with heterozygous Familial hypercholesterolemia (HeFH), a severe genetic hyperlipidemia (Vairo et al., 2021). In this project, we would like to extend the characterization of A2AR expression in a larger cohort of patients with hypercholesterolemia (including heterozygous and homozygous FH and polygenic hypercholesterolemia) before and after hypocholesterolemic treatments and to understand whether 1) alterations of A2AR expression are broadly associated with hypercholesterolemia; 2) there is a correlation among A2AR expression, blood T-C and LDL-C levels and patient's clinical status; 3) all A2AR alterations may be rescued by hypocholesterolemic treatments. Hypercholesterolemic patients and healthy subjects are selected by age, gender and clinical status, including blood cholesterol levels (T-C > 240 mg/dL and/or LDL-C > 190 mg/dL). A2AR expression was explored in PBMCs by western blot and cytometry. We show on a small number of patients a decrease in A2A receptors expression compared with healthy subjects and an inverse correlation between A2AR expression and total- and LDL-cholesterol blood levels. Our results suggest that alterations of A2A receptors expression are associated with hypercholesterolemia and might help to better understand the high cardiovascular risk in hypercholesterolemia patients.