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As a hallmark of heart disease, cardiac fibrosis contributes to the development of heart failure and arrhythmias and forms a key therapeutic target. There is a major unmet need for selective, potent, and safe antifibrotic drugs. Earlier studies revealed a cardiac fibrosis phenotype in relaxin-1-deficient mice. Recent studies in several rodent models of cardiac fibrosis have documented reversal of fibrosis by treatment with relaxin peptide or virally mediated relaxin gene delivery. In mice with surgically induced transmural myocardial infarction, relaxin therapy inhibited scar density. In these studies, however, functional benefits achieved by relaxin therapy were limited or less explored. Collectively, there is good experimental evidence that relaxin is able to reverse cardiac fibrosis due to distinct mechanisms. Future research needs to explore functional improvement following fibrosis reversal by relaxin and the usefulness of relaxin in antiarrhythmic or stem cell-based therapy. [ABSTRACT FROM AUTHOR]

Although RXFP1-cAMP signaling in HEK293T cell systems is now relatively well-defined, the signaling pathways activated by relaxin in its target cells and tissues are still unclear. This study aimed to examine the cAMP signaling of RXFP1 in cells that endogenously express the receptor. Seven cell types derived from various backgrounds were screened for receptor expression. Only in THP-1 cells and rat cardiac fibroblasts was there activation of the Gαi3–Gβγ–phosphatidylinositol 3-kinase–protein kinase Cζ pathway, leading to cAMP accumulation. In all other cells there was activation of a combination of the initial pathways to affect cAMP. T-47D cells could activate only Gαs, whereas Colo 16 and rat renal fibroblasts from obstructed kidney could activate both Gαs and GαoB pathways. Thus, the signaling pathways activated by relaxin are highly dependent upon the cell type under investigation, and this may help to explain the varied physiological responses exerted by relaxin in its different target tissues. [ABSTRACT FROM AUTHOR]

Cardiac RXFP1 was upregulated upon activation of the α1-adrenergic receptor (AR) through signal pathways involving protein kinase A and C and ERK. In contrast, β1-AR activation downregulated expression of cardiac RXFP1 and it further counteracted the α1-AR-mediated RXFP1 upregulation. [ABSTRACT FROM AUTHOR]