Abstract P1083: Retinoid Regulation Of Cardiac Inflammation

Abstract

Survivors of acute cardiac events (e.g., myocardial infarction, MI) often recover poorly due to pathological remodeling and progressive heart failure. Cell-based therapies hold potential to improve recovery but have had limited success. Our lab has found that infusion of highly proliferative cardiac cell clones from patient biopsies can improve recovery from MI in mice, but with variable efficacy stemming from unknown factors. Because Vitamin A (VA) stores are known to be mobilized to the heart in response to MI, we investigated the effect of VA on patient-derived cardiac cells. Clones were cultured and treated with 500 nanomolar retinoic acid (RA, bioactive metabolite of VA) for 48 hours. Protein was extracted and digested for proteomic analysis using liquid chromatography and mass spectrometry. To investigate interaction of RA with pro-regenerative epidermal growth factor (EGF) family receptor signaling, cells were treated with 50ng/ml recombinant neuregulin (NRG1) alone or in co-treatment with RA. Treatment with RA caused significant increase in protein expression of inflammatory mediators including IL1A/B, ICAM1, prostaglandin synthase, and NFkB2, and less studied targets including differentiation factor latexin (LXN) and orphan G-protein coupled receptor GPRC5A. Expression was validated at the transcript level. NRG1 treatment significantly modulated expression of metabolic regulators carnitine-palmitoyl transferase, phosphofructokinase, and dipeptidyl peptidase but was inhibited by co-treatment with RA. Our data suggest that RA may induce a pro-inflammatory phenotype in proliferative cardiac cells and that RA inhibits pro-regenerative NRG1/EGF receptor signaling, perhaps as part of an emergency inflammatory response to injury. While the biology underlying limited successes of cell therapies to treat heart disease is incompletely understood, managing inflammation is one strategy that has shown benefits in treatment of heart failure and reprogramming cells to therapeutic ends. Further experiments are called for to investigate an inflammatory role of VA during MI in vivo, and to determine how the interaction of VA and NRG1 may regulate proliferative cardiac cell fate and function after injury.