Cardioprotective effects of small-molecule ErbB4 activation are sex-specific and oestrogen dependent

Recently, a small-molecule ErbB4 agonist (EF-1) showed reduction of post-infarction remodelling and attenuation of cell death after induced cardiotoxicity in mice. Remarkably, these significant cardioprotective effects were only present in female mice. The sex-specific differences in treatment outcome might be due to an oestrogen driven co-activation of oestrogen receptor α and ErbB4 - a phenomenon previously described in different cell types, but not yet explored in cardiac cells. Since EF-1 has been welcomed as a promising novel heart failure treatment, it is important to explore potential sex-differences in treatment-response to further develop its therapeutic potential.

In order to investigate potential synergy between ErbB4- and oestrogen signalling, this study design both included intact and ovariectomised female mice. As oestrogen signalling exerts strong intrinsic cardioprotective effects, this design enables us to distinguish genuine interactions from non-specific improvement of cardiovascular disease attributable solely to oestrogen exposure.

For a myocardial infarction (MI) model and an acute anthracycline cardiotoxicity (DOX) model, female mice were randomly assigned to one of two groups. One group underwent ovariectomy (Ovx), while the other received a sham surgery. 6 weeks later, mice were randomly assigned to one of three groups: a control group (Ctrl) receiving neither intervention nor treatment, a vehicle (Veh) group undergoing intervention (either MI surgery or anthracyclin exposure) and receiving control vehicle through subcutaneous minipumps, and a treatment group (EF-1) undergoing intervention and receiving EF-1 through minipumps. For either model, appropriate data was collected regarding cardiac remodelling (MI model) and cell death (DOX model).

In the MI model, no treatment effect of EF-1 on left ventricular end-diastolic volume was observed in ovariectomized females (EF-1 vs. Veh: 106.4±25.18µL vs. 105.5±14.93µL, p=0.9956) as opposed to intact mice (EF-1 vs. Veh: 90.09±17.07µL vs.120.4±27.73µL, p=0.0111). Fibrotic remodelling, quantified on Masson’s Trichrome stain, was significantly decreased in the myocardium of intact treated mice (EF-1 vs. Veh: 2.394±0.71% vs.3.608±1.3%, p=0.0092), but not in ovariectomised mice (EF-1 vs. Veh: 2.256±0.79% vs. 1.856±0.58%, p=0.6575). In the DOX model, plasma concentrations of cardiac troponin I were significantly decreased in intact treated mice (EF-1 vs. Veh: 13.55±5.25 vs.19.97±3.57, p=0.0003), but not in ovariectomised mice (EF-1 vs. Veh: 15.38±2.93 vs.18.23±2.12, p=0.2244).

The reduction of circulating oestrogens through ovariectomy significantly decreased the cardioprotective effects of EF-1 in two distinct in vivo models. This suggests a pivotal role for oestrogen signalling in the treatment response to novel small-molecule ErbB4 agonists, the precise subcellular mechanisms of which warrant further investigation.For image description, please refer to the figure legend and surrounding text.  For image description, please refer to the figure legend and surrounding text.