Abstract 16460: Deletion of Aryl Hydrocarbon Receptor Nuclear Translocator (HIF1-β) in the Heart Leads to Cardiomyopathy and Lipid Accumulation via PPARα
Background: Patients with type 2 diabetes are prone to cardiovascular complications, including high rates of lipid uptake and accumulation in cardiomycoytes. However, the mechanism for lipid build up in the heart is not totally clear. Aryl hydrocarbon 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 ARNT deletion in the heart 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. csARNT-KO mice displayed enlarged left ventricle and reduced ejection fraction compared to controls (35.8±3.6% vs. 61.2±2.8%, n=12, p<0.01). Electron microscopy revealed lipid droplets in csARNT-KO hearts that were confirmed by oil-red staining and measurement of triglyceride levels. Consistent with the gene expression profile, the ex-vivo working hearts showed 2 fold increase in fatty acid oxidation. To study the mechanism for increased lipid accumulation in csARNT-KO mice, we measured the levels of PPAR proteins. PPARα and its target genes were significantly increased in the csARNT-KO hearts. The mechanism for the regulation of PPARα by ARNT is at transcriptional levels, as ARNT knockdown resulted in increased PPAR promoter activity in a luciferase reporter assay, and increased PPARα protein and its target genes in isolated cardiomyocytes. Finally, to confirm that the effects of ARNT downregulation on cardiac metabolism are through PPARα, we downregulated both ARNT and PPARα in isolated cardiomyocytes and showed that knockdown of PPARα reverses the lipotoxicity associated with ARNT reduction.
Conclusion: These results suggest that ARNT is critical regulator of myocardial fatty acid metabolism, and a reduction in ARNT levels leads to cardiomyopathy by increasing lipid accumulation through a PPAR pathway.
- © 2012 by American Heart Association, Inc.