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Stimulation of ?-adrenoceptors up-regulates cardiac expression of galectin-3 and BIM through the Hippo signalling pathway.

ABSTRACT: BACKGROUND AND PURPOSE:Expression of the pro-fibrotic galectin-3 and the pro-apoptotic BIM is elevated in diseased heart or after ?-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 ?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 ?-adrenoceptor agonist isoprenaline or ?-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 ?-adrenoceptor antagonists (by 60-70%). Cardiac expression of galectin-3 and BIM was increased in ?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 ?-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 ?-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.

SUBMITTER: Zhao WB

PROVIDER: S-EPMC6592853 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Zhao Wei-Bo WB Lu Qun Q Nguyen My-Nhan MN Su Yidan Y Ziemann Mark M Wang Li-Na LN Kiriazis Helen H Puthalakath Hamsa H Sadoshima Junichi J Hu Hou-Yuan HY Du Xiao-Jun XJ

British journal of pharmacology 20190530 14

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Wild-type mice and mice with cardiac transgenic expression of β<sub>2</sub> -adrenoceptors, mammalian sterile-20 like kinase 1 (Mst1) or dominant-negative Mst1, and non-specific galectin-3 knockout mice were used ...[more]

PMID: 30932177

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Project description:BackgroundThere are three turkey β-adrenoceptors: the original turkey β-adrenoceptor from erythrocytes (tβtrunc, for which the X-ray crystal structure has recently been determined), tβ3C and tβ4C-receptors. This study examined the similarities and differences between these avian receptors and mammalian receptors with regards to binding characteristics and functional high and low affinity agonist conformations.Methodology/principal findingsStable cell lines were constructed with each of the turkey β-adrenoceptors and 3H-CGP12177 whole cell binding, CRE-SPAP production and (3)H-cAMP accumulation assays performed. It was confirmed that the three turkey β-adrenoceptors are distinct from each other in terms of amino acid sequence and binding characteristics. The greatest similarity of any of the turkey β-adrenoceptors to human β-adrenoceptors is between the turkey β3C-receptor and the human β2-adrenoceptor. There are pharmacologically distinct differences between the binding of ligands for the tβtrunc and tβ4C and the human β-adrenoceptors (e.g. with CGP20712A and ICI118551). The tβtrunc and tβ4C-adrenoceptors appear to exist in at least two different agonist conformations in a similar manner to that seen at both the human and rat β1-adrenoceptor and human β3-adrenoceptors. The tβ3C-receptor, similar to the human β2-adrenoceptor, does not, at least so far, appear to exist in more than one agonist conformation.Conclusions/significanceThere are several similarities, but also several important differences, between the recently crystallised turkey β-adrenoceptor and the human β-adrenoceptors. These findings are important for those the field of drug discovery using the recently structural information from crystallised receptors to aid drug design. Furthermore, comparison of the amino-acid sequence for the turkey and human adrenoceptors may therefore shed more light on the residues involved in the existence of the secondary β-adrenoceptor conformation.

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Stimulation of ?-adrenoceptors up-regulates cardiac expression of galectin-3 and BIM through the Hippo signalling pathway.

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

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