Abstract P2061: The Intersection Of O-GlcNAc And Yap - A Novel Molecular Axis In Heart Failure

Abstract

Introduction: Heart failure (HF) and pathological myocardial hypertrophy continue to grow world-wide and are strongly tied to obesity, hyperglycemia, and ischemia. These stressors lead to increased levels of O-beta-N-Acetylglucosamine modified proteins (OGN) in the heart. OGN levels are determined by the net activity of two enzymes, OGT and OGA. Our recent work showed excessive OGN was sufficient to cause HF and pathological myocardial hypertrophy. Here we test the relationship between OGN and Yes Associated Protein (YAP), a known promoter of cardiac hypertrophy. Objectives: Test if OGN modifies YAP in the heart and evaluate the role of OGN modified YAP in the development of pathologic cardiac hypertrophy and heart failure. Methods: We have shown that mouse models with myocardial OGT overexpression (OGT TG) developed pathological cardiac hypertrophy and HF. We found these animals have increased YAP activity. Myocardial OGA overexpression (OGA TG) attenuated OGN following transaortic constriction(TAC) and were protected against cardiac hypertrophy and HF. Interbreeding OGT TG with OGA TG rescued animals from pathological hypertrophy, HF and normalized YAP activity . We quantified levels of activated YAP protein/gene expression in hearts from WT, OGT, OGA and OGT x OGA mice. We evaluated YAP/TEAD1 target gene expression levels in OGA TG mice protected against TAC. We used an adenoviral YAP/TEAD expression reporter to quantify YAP/TEAD1 activity in cardiac myocytes, in the presence and absence of increased O-GlcNAcylation. Results: We found WT levels of activated (nuclear) YAP in OGA TG, increased active YAP in OGT TG and normal levels in OGT x OGA mice. YAP/TEAD1 target genes are upregulated in OGT TG hearts but interbred OGT x OGA animals have normal cardiac function and YAP/TEAD1 target gene expression. OGA TG mice who are protected against TAC induced heart failure/hypertrophy and have decreased myocardial levels of YAP/TEAD1 gene targets involved in pathological hypertrophy. Increased O-GlcNAcylation in cardiac myocytes activates YAP/TEAD activity and YAP/TEAD downstream gene expression. Conclusion: These preliminary data suggest a novel pathway for promoting pathological hypertrophy and HF via activation of the O-GlcNAc -YAP/TEAD1 axis.