β-arrestin2 in Infiltrated Macrophages Inhibits Excessive Inflammation after Myocardial Infarction

Beta-arrestins (beta-arrestin1 and beta-arrestin2) are known as cytosolic proteins that mediate desensitization and internalization of activated G protein-coupled receptors. In addition to these functions, beta-arrestins have been found to work as adaptor proteins for intracellular signaling pathways. beta-arrestin1 and beta-arrestin2 are expressed in the heart and are reported to participate in normal cardiac function. However, the physiological and pathological roles of beta-arrestin1/2 in myocardial infarction (MI) have not been examined. Here, we demonstrate that beta-arrestin2 negatively regulates inflammatory responses of macrophages recruited to the infarct area. beta-arrestin2 knockout (KO) mice have higher mortality than wild-type (WT) mice after MI. In infarcted hearts, beta-arrestin2 was strongly expressed in infiltrated macrophages. The production of inflammatory cytokines was enhanced in beta-arrestin2 KO mice. In addition, p65 phosphorylation in the macrophages from the infarcted hearts of beta-arrestin2 KO mice was increased in comparison to that of WT mice. These results suggest that the infiltrated macrophages of beta-arrestin2 KO mice induce excessive inflammation at the infarct area. Furthermore, the inflammation in WT mice transplanted with bone marrow cells of beta-arrestin2 KO mice is enhanced by MI, which is similar to that in beta-arrestin2 KO mice. In contrast, the inflammation after MI in beta-arrestin2 KO mice transplanted with bone marrow cells of WT mice is comparable to that in WT mice transplanted with bone marrow cells of WT mice. In summary, our present study demonstrates that beta-arrestin2 of infiltrated macrophages negatively regulates inflammation in infarcted hearts, thereby enhancing inflammation when the beta-arrestin2 gene is knocked out. beta-arrestin2 plays a protective role in MI-induced inflammation.