The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor α (RORα), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORα is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORα. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K) / Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.

Mangiferin and mangiferin-containing extracts from Mangifera foedita leaves are potent candidates as antioxidant iron chelators in the management of iron-overloaded thalassemia patients and may help to lower the costs of their treatment.

Tumor suppressor protein p53 plays crucial roles in the onset of heart failure. p53 activation results in cardiac dysfunction, at least partially by suppressing angiogenesis. Though p53 has been reported to reduce VEGF production by inhibiting hypoxia‐inducible factor, the anti‐angiogenic property of p53 remains to be fully elucidated in cardiomyocytes. To explore the molecular signals downstream of p53 that regulate vascular function, especially under normoxic conditions, DNA microarray was performed using p53‐overexpressing rat neonatal cardiomyocytes. Among genes induced by more than 2‐fold, we focused on CXCL10, an anti‐angiogenic chemokine. Real‐time PCR revealed that p53 upregulated the CXCL10 expression as well as p21, a well‐known downstream target of p53. Since p53 is known to be activated by doxorubicin (Doxo), we examined the effects of Doxo on the expression of CXCL10 and found that Doxo enhanced the CXCL10 expression, accompanied by p53 induction. Importantly, Doxo‐induced CXCL10 was abrogated by siRNA knockdown of p53, indicating that p53 activation is necessary for Doxo‐induced CXCL10. Next, we examined the effect of hypoxic condition on p53‐mediated induction of CXCL10. Interestingly, CXCL10 was induced by hypoxia and its induction was potentiated by the overexpression of p53. Finally, the conditioned media from cultured cardiomyocytes expressing p53 decreased the tube formation of endothelial cells compared with control, analyzed by angiogenesis assay. However, the inhibition of CXCR3, the receptor of CXCL10, restored the tube formation. These data indicate that CXCL10 is a novel anti‐angiogenic factor downstream of p53 in cardiomyocytes and could contribute to the suppression of vascular function by p53.