Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy

Rongxue Wu, Hsiang Chun Chang, Arineh Khechaduri, Kusum Chawla, Minh Tran, Xiaomeng Chai, Cory Wagg, Mohsen Ghanefar, Xinghang Jiang, Marina Bayeva, Frank Gonzalez, Gary Lopaschuk, Hossein Ardehali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1β) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPARα and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPARα mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2α. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPARα.

Original languageEnglish (US)
Pages (from-to)4795-4806
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number11
DOIs
StatePublished - Nov 3 2014

ASJC Scopus subject areas

  • Medicine(all)

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