Abstract
Increased protein O -GlcNAcylation (OGN) is a common feature of failing heart muscle. However, it is unknown if excessive OGN contributes to cardiomyopathy and heart failure. OGN levels are determined by the net activity of two enzymes: OGT ( O -GlcNAc transferase, adds OGN) and OGA ( O -GlcNAcase, removes OGN). We hypothesized that excessive myocardial OGN is a cause of cardiomyopathy. To test for a role of OGN in cardiomyopathy we developed new transgenic (TG) mouse models with myocardial overexpression of OGT or OGA. The OGT-TG hearts showed progressive decline in left ventricular (LV) systolic function, dilation, increased mass (Figure A, B) (Statistical Analysis ANOVA - *** = p<0.001) and increased OGN (Figure C) . OGT-TG mice showed premature mortality compared to WT littermates (Figure D). In contrast, OGA-TG mice exhibit normal contractility, do not have significantly different OGN and have normal lifespan compared to WT littermates. Hearts from OGT-TG and OGA-TG interbred mice have marked improvement of LV systolic function, lower OGN and normal lifespan. We next tested if attenuation of myocardial OGN was beneficial in acquired cardiomyopathy by performing transverse aortic constriction surgery (TAC) on OGA-TG and WT littermates. The OGA-TG hearts had lower OGN, improved LV systolic function, less hypertrophy, and lower expression of heart failure genes compared to WT littermates after TAC. Our data identify excessive OGN as an independent mechanism for cardiomyopathy, and suggest attenuation of OGN may be an effective therapy for heart failure.
Published Version
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