Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy
Rongxue Wu, … , Gary Lopaschuk, Hossein Ardehali
Rongxue Wu, … , Gary Lopaschuk, Hossein Ardehali
Published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):4795-4806. https://doi.org/10.1172/JCI76737.
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Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy

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.

Authors

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

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Figure 3

csArnt–/– hearts display increased lipid accumulation.

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csArnt–/– hearts display increased lipid accumulation. (A) Representativ...
(A) Representative cardiac histological sections of control (Arntfl/fl littermates) and csArnt–/– mice 4 weeks after initiation of tamoxifen treatment. MT, Masson’s trichrome. Scale bars: 1 mm (H&E-stained ×4 images) and 100 μm (H&E-stained ×200 and MT-stained images). Experiments were repeated 3 times. (B) TUNEL staining of hearts from control and csArnt–/– mice. TUNEL+ cells were normalized to the total number of nuclei and are represented as a bar graph next to the images (n = 6 independent experiments). Scale bars: 500 μm. (C) Electron microscopic images of control and csArnt–/– hearts indicated the presence of fat droplets. Red arrows point to lipid vacuoles in the csArnt–/– hearts. Scale bars: 1 μm (×4,800 images) and 500 nm (×9,300 images). (D) Oil red O staining of control and csArnt–/– hearts. Scale bars: 500 μm (original magnification, ×100 and ×500 [insets]). Experiments were repeated 3 times. (E) Summary bar graph of images in D (n = 3 independent experiments). (F) TAG content in the heart of control and csArnt–/– mice (n = 6 independent experiments). Data are presented as the mean ± SEM. *P < 0.01.