Abstract 14164: ARNT/HIF1β Deletion in the Heart Leads to a Phenotype That Mimics Diabetic Cardiomyopathy Through Activation of PPARa
Background: Diabetic cardiomyopathy is associated with high rates of lipid uptake and accumulation in the heart, however, the mechanism for this phenomenon is not totally clear. Aryl hydrocarbon receptor nuclear translocator (ARNT), also known as hypoxia-inducible factor-1β (HIF1β), is a transcription factor that regulates several cellular processes by dimerizing with certain proteins, including HIF-1α or -2α. Liver- or pancreas-specific ARNT knockout in mice leads to a phenotype that mimics type 2 diabetes, but the role of ARNT in cardiac function and metabolism is not known. We hypothesized that cardiac deletion of ARNT leads to metabolic derangement and cardiac dysfunction.
Methods and Results: Cardiac-specific ARNT knockout (csARNT-KO) mice were generated by crossing ARNTflox/flox with tamoxifen-inducible heart-specific Cre mice, followed by oral administration of tamoxifen. ARNT deletion in the heart resulted in enlarged left ventricle and reduced ejection fraction compared to controls. Electron microscopy revealed lipid droplet accumulation in csARNT-KO hearts that were confirmed by oil-red staining and elevation of cardiac triglyceride levels. Furthermore, studies in ex-vivo working hearts showed a 2-fold increase in fatty acid oxidation (FAO). To study the mechanism for increased lipid accumulation in csARNT-KO mice, we assessed the levels of PPAR proteins, and found that only PPARα was significantly higher in the csARNT-KO hearts. ARNT knockdown resulted in increased PPARα promoter activity measured by a luciferase reporter assay, and increased PPARα protein and its target genes in isolated cardiomyocytes, suggesting that the mechanism for the regulation of PPARα by ARNT is at the transcriptional level. Finally, mice with double deletion of ARNT and PPARα displayed restoration of cardiac function, improved survival, and complete reversal of FA accumulation.
Conclusion: Our data indicate that a reduction in ARNT levels leads to cardiomyopathy by increasing lipid accumulation through a PPARα pathway. Thus, ARNT is a critical regulator of fatty acid metabolism in the heart, and a potential target for treatment of diabetic cardiomyopathy.
- © 2013 by American Heart Association, Inc.