GHSR deficiency exacerbates cardiac fibrosis: role in macrophage inflammasome activation and myofibroblast differentiation

AIMS: Sustained activation of beta-adrenergic signaling induces cardiac fibrosis, which marks progression to heart failure. GHSR (growth hormone secretagogue receptor) is the receptor for ghrelin, which is an orexigenic gastric hormone with newly defined cardiovascular effects. The present study determined the effects of GHSR deficiency in a mouse model of isoproterenol (ISO)-induced cardiac fibrosis and examined the underlying mechanism. METHODS AND RESULTS: Histochemical studies showed that GHSR deficiency exacerbated cardiac fibrosis. Quantitative RT-PCR, western blotting and immunofluorescence staining demonstrated that cardiac fibroblasts isolated from GHSR-/- mice exhibited increased expression of marker genes for myofibroblast trans-differentiation (alpha-SMA, SM22, and calponin) upon Transforming growth factor-beta (TGF-beta) treatment compared to wild-type mice. RNA-Sequencing of heart transcriptomes revealed that differentially expressed genes in GHSR-/- hearts were enriched in such biological processes as extracellular matrix (ECM) organization, inflammatory response, lipid metabolism, cell cycle, migration and adhesion. Particularly, GHSR deficiency increased Wnt/beta-catenin pathway activation in ISO-induced myocardial fibrosis. In addition, loss of GHSR in macrophages instigated inflammasome activation with increased cleavage and release of IL-18. CONCLUSIONS: These results for the first time demonstrated that GHSR deficiency aggravated ISO-induced cardiac fibrosis, suggesting that GHSR was a potential target for the intervention of cardiac fibrosis. TRANSLATIONAL PERSPECTIVE: We revealed a cardiac protective role of GHSR, a receptor for gastric hormone ghrelin. Our study provided a novel therapeutic strategy against cardiac fibrosis.