NEGATIVE IMPACT OF BETA-ARRESTIN1 ON HEART FAILUREVIA CARDIAC AND ADRENAL DEPENDENT MECHANISMS

Objective. Investigation of beta-arrestin1 (barr1) in post-myocardial infarction (MI) heart failure (HF). Background. barrs are universal G protein-coupled receptor adapter proteins that negatively regulate cardiac betaadrenergic receptor (betaAR) function via betaAR desensitization & downregulation. In addition, they mediate G protein-independent betaAR signaling, which might be beneficial, e.g. antiapoptotic, for the heart. However, the specific role(s) of each barr isoform in cardiac betaAR dysfunction, the molecular hallmark of chronic HF, remain unknown. Furthermore, adrenal barr1 exacerbates HF by chronically enhancing adrenal production, and hence circulating levels of aldosterone and catecholamines. Methods. We studied barr1 knockout (barr1KO) mice alongside wild type (WT) controls under normal conditions and after surgical MI. Results. Normal (sham-operated) barr1KO`s display enhanced betaAR-dependent contractility and post-MI barr1KO`s enhanced overall cardiac function (and betaAR-dependent contractility) compared to WT`s. Post-MI barr1KO`s also show increased survival, and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines & aldosterone, compared to post-MI WT`s. The underlying mechanisms are on one hand improved cardiac betaAR signaling and function, as evidenced by increased betaAR density and pro-contractile signaling, via reduced cardiac betaAR desensitization due to cardiac barr1 absence, and on the other hand decreased production leading to lower circulating levels of catecholamines & aldosterone due to adrenal barr1 absence. Conclusion. Thus, barr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF. Grants. 1) Scientist Development Grant from the American Heart Association (AHA #09SDG2010138, National Center) to A.L. 2)NSU HPD Research Grant #335797 to A.