P2Y4 nucleotide receptor: A novel target for anti-inflammatory therapies to improve myocardial infarction outcome

Abstract

Human P2Y4 is a UTP receptor, while in mice it is activated by both ATP and UTP. P2Y4 knockout (KO) in mice protects against myocardial infarction and leads to increased adiponectin secretion by adipocytes and lower cardiac inflammation under ischemia. The main objective is to investigate the anti-inflammatory mechanisms of cardioprotection in P2Y4 KO ischemic mice, and explore the relevance of these data in humans. We performed left anterior descending artery ligation on wild-type and P2Y4 KO mice to investigate the inflammatory state of their pericardial adipose tissue under ischemia. In parallel, in a population study comprising patients with coronary artery disease (CAD) and age-matched control individuals, we analyzed P2RY4 gene mutations and their potential association with CAD severity and fasting plasma parameters. We demonstrated that P2Y4 KO mice displayed adipocyte beiging with increased PD-L1 expression and a higher number of regulatory leukocytes in their pericardial adipose tissue after left anterior descending artery ligation, compared to wild-type mice. Interestingly, the reduction of T cell infiltration and cardiac fibrosis observed in P2Y4 KO heart was lost after injection of anti-PD-L1 blocking antibody in ischemic mice. We also identified a N178T loss-of-function mutation of the human P2Y4 receptor found less frequently in CAD patients than in control individuals. In coronary patients, carriers of the N178T variant had significantly reduced Duke jeopardy and Gensini cardiac severity scores, as well as lower resting heart rates and reduced plasma levels of N-terminal pro-brain natriuretic peptide and fasting glucose. Accordingly, P2Y4 KO mice had significantly improved glucose tolerance and insulin sensitivity compared with their wild-type littermate controls. The present study defines P2Y4 receptor as a negative regulator of PD-L1 and adiponectin, and as a potential target for anti-inflammatory therapies. The combined effect of P2Y4 loss on adipocyte beiging and regulatory leukocyte increase highlights this nucleotide receptor as an important player in post-ischemic cardiac response. We also identified a frequent loss-of-function P2Y4 variant associated with less severe coronary artery atherosclerosis and lower fasting plasma glucose in CAD patients. P2Y4 antagonists could thus have therapeutic applications in the treatment of myocardial infarction and type 2 diabetes.