Stimulation of β‐adrenoceptors up‐regulates cardiac expression of galectin‐3 and BIM through the Hippo signalling pathway

BACKGROUND AND PURPOSE: Expression of the pro‐fibrotic galectin‐3 and the pro‐apoptotic BIM is elevated in diseased heart or after β‐adrenoceptor stimulation, but the underlying mechanisms are unclear. This question was addressed in the present study. EXPERIMENTAL APPROACH: Wild‐type mice and mice with cardiac transgenic expression of β(2)‐adrenoceptors, mammalian sterile‐20 like kinase 1 (Mst1) or dominant‐negative Mst1, and non‐specific galectin‐3 knockout mice were used. Effects of the β‐adrenoceptor agonist isoprenaline or β‐adrenoceptor antagonists were studied. Rat cardiomyoblasts (H9c2) were used for mechanistic exploration. Biochemical assays were performed. KEY RESULTS: Isoprenaline treatment up‐regulated expression of galectin‐3 and BIM, and this was inhibited by non‐selective or selective β‐adrenoceptor antagonists (by 60–70%). Cardiac expression of galectin‐3 and BIM was increased in β(2)‐adrenoceptor transgenic mice. Isoprenaline‐induced up‐regulation of galectin‐3 and BIM was attenuated by Mst1 inactivation, but isoprenaline‐induced galectin‐3 expression was exaggerated by transgenic Mst1 activation. Pharmacological or genetic activation of β‐adrenoceptors induced Mst1 expression and yes‐associated protein (YAP) phosphorylation. YAP hyper‐phosphorylation was also evident in Mst1 transgenic hearts with up‐regulated expression of galectin‐3 (40‐fold) and BIM as well as up‐regulation of many YAP‐target genes by RNA sequencing. In H9c2 cells, isoprenaline induced YAP phosphorylation and expression of galectin‐3 and BIM, effects simulated by forskolin but abolished by PKA inhibitors, and YAP knockdown induced expression of galectin‐3 and BIM. CONCLUSIONS AND IMPLICATIONS: Stimulation of cardiac β‐adrenoceptors activated the Mst1/Hippo pathway leading to YAP hyper‐phosphorylation with enhanced expression of galectin‐3 and BIM. This signalling pathway would have therapeutic potential. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc