Therapeutic Efficacy of a Novel Pharmacologic GRK2 Inhibitor in Mice Models of Heart Failure

Abstract

<b>Abstract ID 52525</b> <b>Poster Board 104</b> <b>Background:</b> GRK2 is an abundantly expressed GRK in the heart and plays a crucial role in the pathogenesis of heart failure. Targeting GRK2 in HF has been previously reported to be cardioprotective in mouse models of HF, genetically with βARKct and with paroxetine an FDA-approved SSRI that also has potent GRK2 inhibitory properties. To enhance the GRK2 inhibitory properties of paroxetine while still retaining its selectivity a library of compounds was generated based on its scaffold. Amongst them, the14as compound had 50-fold higher selectivity for GRK2 and increased myocyte contractile function in&nbsp;vitro at doses 100-fold lower than paroxetine. Such profound in&nbsp;vitro effects led to its evaluation in heart failure models in&nbsp;vivo. <b>Aim:</b> To evaluate cardioprotective effects and an ideal dose of 14as in two different mouse injury models of heart failure. <b>Methods:</b> 14as was first evaluated in a mouse model of myocardial infarction (MI). 2 weeks post-MI, three different doses of 14as – high 2mg/kg/day, medium 0.5mg/kg/day and low 0.1mg/kg/day were administered via osmotic pumps. Cardiac function and LV (left ventricular) chamber dimensions were measured by echocardiography. After concluding the ideal dose of 14as in an MI model, 14as was evaluated in a transverse aortic constriction (TAC) model for its cardioprotective properties. Similar to the MI model, 14as was delivered via osmotic pumps, and cardiac function was evaluated by echocardiography starting at 2 weeks up to 12 weeks post-TAC. <b>Results:</b> From the three doses evaluated in the MI model, both the high and the medium doses were cardioprotective. Both groups had significantly higher ejection fraction (EF) and fractional shortening (FS) with the high dose being better and near identical to the effects of paroxetine. The high-dose treated hearts displayed a smaller LV lumen size, smaller LV inner diameter at systole (LVID;s), and displayed a lower heart weight/body weight ratio and lower lung weight compared to the vehicle group, 6 weeks post MI. Post TAC hearts treated with 14as also had significantly higher EF and FS compared to the control group and a lower LV mass, LVID;s, smaller LV blood volume at end systole (Vol;s), and lower heart weight/body weight ratio compared to the control group. <b>Conclusion:</b> In two fundamentally different injury models of heart failure, high dose 14as not only arrested declining contractile function but also reversed it and attenuated adverse LV remodeling. Being structurally similar to paroxetine it will potentially exhibit a similar safety profile in humans and can be explored as a potential new drug for heart failure in clinical trials. This research was funded by R01 HL061690 and NIH/NHLBI 5R01HL071818-18