CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor

Abstract

Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.

Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy

“…To reactivate CXCR7 signaling, we treated our cKO mice with the CXCR7 agonist TC14012, which attenuated the severe hypertrophic phenotype and improved heart function (see also Figure 7 ). As a potential downstream target for CXCR7 signaling, we identified increased pERK signaling, which has also been reported previously [ 54 , 57 , 59 ]. CXCL12 signaling directly via CXCR7 is Gαi-receptor-independent, and activation of pERK could lead to cell survival and chemotaxis [ 60 ].…”

“…Alternatively, CXCR7 can also form heterodimers with the CXCR4 receptor regulating G-protein-mediated signal transduction [ 4 , 56 ]. A recent study has shown that CXCR7 expression is elevated in human heart failure and hypothesized that it might have cardioprotective effects [ 57 ]. Mechanistically the authors also demonstrated that CXCR7 acts through β-arrestin-mediated pERK signaling.…”

“…Mechanistically the authors also demonstrated that CXCR7 acts through β-arrestin-mediated pERK signaling. Several preclinical animal models have proven that CXCR7 activation has a protective role in acute MI and atherosclerotic vascular diseases [ 6 , 57 , 58 ]. To reactivate CXCR7 signaling, we treated our cKO mice with the CXCR7 agonist TC14012, which attenuated the severe hypertrophic phenotype and improved heart function (see also Figure 7 ).…”

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

“…At present, one can only speculate a few possibilities. Expression of ACKR3/CXCR7 is significantly increased at the infarct border zone of myocardium [ 26 , 27 , 28 ], and peri-infarct regions of the brain [ 29 ] in animal models [ 27 , 28 , 30 , 31 ] and humans alike [ 26 , 28 , 32 ]. Firstly, target organ (e.g., myocardium) specific expression of ACKR3/CXCR7 might either override or be complemented by the impact of platelet ACKR3/CXCR7 in the repair and regenerative mechanisms.…”

“…Since activated platelets infiltrate ischemia affected myocardium [ 5 , 7 , 33 , 34 ], they can actively regulate the balance between inflammation vs regeneration [ 7 ]. The extent to which platelet ACKR3/CXCR7 may influence this functional outcome, superseding the acclaimed regenerative drive of ACKR3/CXCR7 highly expressed in cardiomyocytes [ 26 ] and endothelial cells [ 27 ], is uncertain. Cardiomyocytes, like circulating platelets [ 22 ], exhibit increased expression of CXCL12/SDF1α following MI, which significantly influences the migration of CXCR4 and ACKR3/CXCR7 expressing cardiac stem cells with regenerative potential [ 35 ] as observed in murine models.…”