Abstract P006: A Potential Role for β-Arrestins in Cardiac Regeneration

Abstract

Development of chronic heart failure (HF) syndrome following myocardial injury (MI) is characterized by an extensive loss of myocytes due to substantial apoptosis and necrosis. As bone marrow derived stem cells (BMSCs) are capable of transdifferentiating, they also show potential for regenerating the myocardium after infarction. Stem cell mobilization, egress from the bone marrow and homing to the site of injury can be regulated by signals through G protein-coupled receptors (GPCRs). β-arrestins are known for their signalling and scaffolding functions and as downstream regulators of GPCR desensitization and endocytosis in particular. We have begun to investigate whether β-arrestins play any role in cardiac precursor cell function concentrating on the properties of BMSCs. Using knockout (KO) mice, we investigated the role β-arrestin1 (βArr1) and β-arrestin2 (βArr2) with respect to modulation of regenerative competence of BMSCs and their contribution to cardiac repair following ischemic injury. First, BM-derived cells devoid of either βArr1 or βArr2 were found to proliferate and colonize in a significantly deficient manner compared to BM cells isolated from wild-type (WT) mice. In addition, the number of c-kit positive cardiac stem cells (as a % of total BM) were significantly lower in the βArr KO mice compared to WT. We carried out BM transplant studies to begin to determine whether the βArrs may play a role in cardiac repair. In our study, WT mice were irradiated and then received BM transplants from either WT donors as a control or BM from βArr1 or βArr2 KO mice. Subsequent to BM reconstitution, mice underwent a myocardial infarction (MI) and their condition was followed. Interestingly, chimeric mice with βArr1 and βArr2 KO BM had significantly poorer outcomes than mice receiving WT BM. This included significantly decreased post-MI survival with βArr2 KO BM and both βArr chimeras had significantly lower cardiac function post-MI compared to mice receiving WT BM. Additionally, our analyses of the BM cells and very small embryonic-like stem cells (VSELs) circulating in peripheral blood (PB), indicate that βArr-KO BM and PB contain fewer and less viable cardiac stem/precursor cells compared to WT transplanted controls.