Abstract 14413: Genetic Deletion of Cardiomyocyte Glutamine Synthetase in a Model of HF Hints at Cardiomyocyte to Fibroblast Metabolic Crosstalk Mediating Fibrosis

Abstract

Introduction: Recent evidence in heart failure patients revealed a significant release of glutamine from the heart as evidenced by arterial-coronary sinus concentration differences. Interestingly, enhanced glutamine utilization is required for fibroblast to myofibroblast differentiation and persistence in response to stress stimuli. Therefore, the aim of this study was to determine if cardiomyocyte-derived glutamine influences fibroblast activation and fibrosis. Methods: To determine the effects of cardiomyocyte glutamine production in the failing heart, glutamine synthetase floxed mice (GS fl/fl ) were bred with the cardiomyocyte-specific, tamoxifen-activated Cre mice (MCM). (GS catalyzes the condensation of glutamate to glutamine.) GS fl/fl x MCM and MCM controls were fed tamoxifen chow for 1w followed by a 1w washout. Western blotting confirmed cardiomyocyte GS deletion and baseline LV function was assessed by echocardiography, followed by randomization to sham or TAC surgery. Cardiac function was tracked at 4, 8, and 12wks post-TAC followed by tissue collection, assessment of gravimetrics, and histological staining. Results: Cardiomyocytes isolated from GS fl/fl x MCM hearts following tamoxifen administration revealed a near complete loss of GS protein. While loss of GS did not impact baseline cardiac function, GS fl/fl x MCM mice were significantly protected against pressure-overload induced cardiac dysfunction indicated by preserved FS% (n=8/group; p<0.0001) and decreased LVESD (n=8/group; p=0.001). Deletion of cardiomyocyte GS did not appreciably impact hypertrophy. To ascertain if the fibrotic response was altered, we performed picrosirius red staining 12w following TAC. Hearts from GS fl/fl x MCM mice showed an ~3-fold reduction in total cardiac fibrosis, as compared to MCM controls. (n=6/group; p=0.01). Conclusions: Our results suggest that cardiomyocyte glutamine synthesis may play a significant role in fibroblast activation and fibrosis in heart failure. Studies are currently underway to identify the precise mechanisms governing metabolic cardiomyocyte to fibroblast crosstalk.