The communication between cardiomyocytes and non-cardiomyocytes in pathophysiological features of heart failure

概要

Heart failure is one of major causes of death in the world. Myocardial injury such as acute myocardial infarction results in cardiomyocyte loss and impairs cardiac function. In response to cardiac dysfunction, neurohumoral factors are produced, and induce cardiac hypertrophy and interstitial fibrosis, defined as cardiac remodeling. It is widely accepted that prevention of cardiac remodeling is a promising therapeutic strategy against heart failure. Here, we focused on two factors, maresin-1 (MaR1) and CXCL10, from the viewpoint of cell-cell communication.

　So far, accumulating evidence has demonstrated that macrophages play important roles in cardiac remodeling by producing cytokines/growth factors. Recently, it has been revealed that macrophages also produce lipid mediators and regulate inflammation; however, the importance of these mediators in cardiovascular diseases remains to be fully addressed. In this study, we examined the pathophysiological significance of MaR1 in cardiomyocytes. MaR1 is a lipid mediator produced from macrophages. MaR1 was originally identified as a member of specialized pro-resolving mediators (SPMs), which suppress the inflammation. By using cultured cardiomyocytes, I demonstrated that MaR1 induced physiological hypertrophy through RORα. Mechanistically, activation of RORα by MaR1 upregulated the expression of IGF- 1, leading to the activation of PI3 kinase/Akt pathway. Importantly, the blockade of these signaling pathways cancelled MaR1-induced cardiomyocyte hypertrophy. Thus, I concluded that MaR1 is a novel mediator that mediates communication between cardiomyocytes and macrophages.

　Vascular dysfunction is closely associated with the onset of heart failure. Since the activation of tumor suppressor p53 in cardiomyocytes causes heart failure, I explored antiangiogenic signaling pathways. After cardiomyocytes were transfected with the adenoviral vector expressing p53 or control vector, the gene expression profile was analyzed by DNA array analysis. As a result, the expression of CXCL10 was upregulated in cardiomyocytes expressing p53. I also demonstrated that doxorubicin, an activator of p53, induced CXCL10. Interestingly, conditioned media from cardiomyocytes expressing p53 suppressed the endothelial cell motility and the blockade of CXCR3, a receptor of CXCL10, restored the cell migration. These data suggest that CXCL10 could mediate the communication between cardiomyocytes and endothelial cells as a detrimental factor in the progression of cardiac remodeling.

　In conclusion, we newly identified MaR1 and CXCL10 as a protective factor and a damaging factor, respectively. These findings would provide novel insights into cell-cell communication that modulates cardiac remodeling, proposing innovative strategies against heart failure.