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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 β2‐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 β2‐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 [ABSTRACT FROM AUTHOR]

Background and Purpose The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. Experimental Approach C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)- CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. Key Results (-)- CGP12177 treatment of healthy mice increased heart rate and left ventricular ( LV) contractility. (-)- CGP12177 treatment of mice subjected to transverse aorta constriction ( TAC), during weeks 4-8 or 4-12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)- CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)- CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. Conclusions and Implications β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. [ABSTRACT FROM AUTHOR]

1: Ivabradine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker If current, thus prolonging the duration of spontaneous depolarization in the sinus node. The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of ß2-adrenergic receptors (ß2AR), or ß-agonist administration. HR and left ventricular fractional shortening (FS) were determined by echocardiography. 2: Initial experiments showed that the conscious restrained state was associated with stress-mediated sympathetic activation, while sympathetic withdrawal occurred under anaesthetized conditions. In wild-type mice, ivabradine reduced HR under both conscious and anaesthetized states, with a similar degree in absolute reduction under both states. FS was unchanged by the treatment. 3: Ivabradine was similarly effective in reducing HR in the ß2AR transgenic mice. Further, ivabradine at 10?mg?kg-1?day-1 reduced the maximal HR increase in response to the ß-agonist isoproterenol, without modifying the response of contractile parameters. 4: These data indicate that oral administration of ivabradine in mice reduces HR while ventricular performance is maintained. This specific HR-reducing action of ivabradine is well preserved under conditions that are associated with significant activation of the sympathoadrenergic system.British Journal of Pharmacology (2004) 142, 107-112. doi:10.1038/sj.bjp.0705696 [ABSTRACT FROM AUTHOR]