Abstract 417: Cardiac Akap12 Signalosome Overexpression Exacerbation of Heart Failure and β-arrestin Signaling Pathway

Abstract

Background: Heart failure (HF) is responsible for 1 out of 8 deaths per year in the U.S.A. andis the major cause of death globally. In HF, chronic β-adrenergic receptor (β-AR)stimulation leads to reduced cardiac function due in part to β-AR desensitization.β-arrestins are proteins that play a major role in desensitizing G protein-coupledreceptors (GPCRs) such as β-AR. Previously we reported enhanced cardiacfunction in mice lacking functional A Kinase Anchoring Protein 12 (AKAP12). Inthis study, we aim to investigate the impact of AKAP12 overexpression(oxAKAP12) on HF progression through assessing β-arrestins. Our central hypothesis is that cardiac AKAP12 overexpression potentiates HF developmentby influencing β-arrestin signaling downstream of the β-AR. Methods: HF was developed in WT and oxAKAP12-Tg mice (8-10) weeks old males andfemales, through chronic Isoproterenol (ISO) administration (60mg/kg/day for 14days). Left ventricular homogenates were used for gene expression analysis.Furthermore, AKAP12 was transiently overexpressed in AC16 cells (humancardiomyocytes cell line), to asses protein expression levels and Gαs pathwayactivity, upon treatment with 100 nM of ISO. Results: Cardiac oxAKAP12 in both males and females reduced left ventricular ejectionfraction (EF) by 14.5±2.5% and fractional shortening (FS) by 22.7±2% after 14-days of chronic ISO treatment when compared to control groups. β-arrestin-1gene expression levels were significantly lower (p=0.022) in oxAKAP12 malehomogenates treated with ISO (14 days) compared to control groups.Interestingly, female homogenates overexpressing AKAP12 showed significantlyhigher β-arrestin-1 gene expression levels (p<0.0001) with ISO treatment,compared to control groups. In AC16 cells overexpressing AKAP12 and treatedwith ISO, Gαs activity and β-arrestin-1 protein expression levels were bothreduced by 50% compared to AC16 ISO treated groups. Conclusion: Cardiac oxAKAP12 negatively influences systolic function in both male andfemale mice, potentially through affecting β-arrestin signaling pathway. Thus,designing novel drugs to inhibit AKAP12 is promising to ameliorate HF.