Myocardial infarction (MI) is an ischemic heart disease caused by occlusion of coronary artery. Previous studies have shown that pH in the hearts decreases to 5.5-6.5 after MI. However, physiological significance of pH reduction remains largely unknown. Therefore, we have studied proton-sensing G protein-coupled receptors (proton-sensing GPCRs) which are activated under low pH condition. So far, four proton-sensing GPCRs have been reported. Among them, GPR4 has the highest expression level in mouse heart. Thus, we studied the role of GPR4 in pathological responses after MI, to elucidate the physiological significance of pH reduction.
We found that GPR4 is highly expressed in vascular endothelial cells which express cell adhesion molecules and promote infiltration of leukocytes. Expression level of cell adhesion molecules was significantly suppressed in GPR4 KO mice. Infiltration of neutrophils and expression of inflammatory cytokines were also suppressed. Cardiac function after MI was improved in GPR4 KO mice compared to WT mice.
In this study, we demonstrated that pH decrease after MI activates GPR4 and induces inflammatory responses leading to heart dysfunction. These results indicate that GPR4 can be a new therapeutic target for the treatment of MI.