Abstract 18219: TGR5 - a Novel Membrane Receptor for Bile Acids Regulates Myocardial Response to Exercise, Catecholamine and Pressure Overload Induced Stress
Introduction: Perturbations in cardiac metabolism precede overt contractile failure and offer an early target for intervention and cure. Novel G protein coupled bile acid membrane receptor TGR5 regulates metabolism and function in brown adipose and skeletal muscles in mice. TGR5 is expressed in the hearts of mice and humans, but its role in myocardial cell biology and stress response is unknown.
Hypothesis: We hypothesize that TGR5 deletion in mouse hearts impairs exercise tolerance, catecholamine response and exaggerates Transverse Aortic Constriction (TAC) induced contractile failure.
Methods: Cardiomyocyte specific TGR5 deleted mice (TGR5flox/flox/cre+ [CM-TGR5del]) were generated from TGR5 floxed mice and transgenic αMHCcre mice. After confirmation of successful deletion at protein and RNA level, 12 week old male CM-TGR5del mice and their littermate (TGR5flox/flox/cre-[WT]) controls underwent baseline echocardiography (2DE), treadmill stress tests, acute catecholamine (isoprenaline [20mcg/kg i.p]) challenge with stress 2DE. Separately, mice underwent TAC or sham for a period of 8 weeks with serial 2DE every 2 weeks. Results: Mean±SD; Stats: ANOVA; p<0.05 is significant; n=5-10/group.
Results: Baseline 2DE parameters were comparable between CM-TGR5del and WT mice. However, on challenge with isoprenaline, peak shortening (47±15 vs 70±9%) and peak ejection fractions (77±14 vs 95±5%) were significantly attenuated in the CM-TGR5del mice compared to WT. On the treadmill, CM-TGR5del mice showed exercise intolerance compared to WT, as evidenced by 50% lesser distance covered (200±65 vs 400±100 m) and earlier fatigue (15±5 vs 30±10 mins), along with lower VO2 max (62 vs 68ml/kg/min). CM-TGR5del mice had a higher mortality (70% vs 30%; p=0.03, Mantel-Cox) and significantly decreased %shortening (10±5 vs 20±7%) 8 wks post TAC compared to WT.
Conclusions: TGR5 deletion impairs cardiac adaptation to stress. Further studies into the role of TGR5 in cardiac pathophysiology are warranted. Targeting TGR5 receptor with readily available natural and synthetic agonists could provide an attractive potential therapy in heart failure.
Author Disclosures: M.S. Desai: Research Grant; Modest; P30 DK056338-11. Z. Eblimit: None. S.J. Karpen: None. D.D. Moore: None. D.J. Penny: None.
- © 2014 by American Heart Association, Inc.