Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy
Rongxue Wu, … , Gary Lopaschuk, Hossein Ardehali
Rongxue Wu, … , Gary Lopaschuk, Hossein Ardehali
Published November 3, 2014; First published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):4795-4806. https://doi.org/10.1172/JCI76737.
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Categories: Research Article Cardiology

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 7

Ppara deletion reverses the cardiac dysfunction of csArnt–/– mice.

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Ppara deletion reverses the cardiac dysfunction of csArnt–/– mice. (A) R...
(A) Representative m-mode echocardiographic images of hearts from control, csArnt–/–, Ppara–/–, and csArnt–/– Ppara–/– double-knockout mice 4 weeks after tamoxifen treatment. The experiment was repeated 7–11 times. (B–D) Echocardiographic data, including cardiac output (CO) (B), FS (C), and EF (D) from control, csArnt–/–, Ppara–/–, and csArnt–/– Ppara–/– double-knockout mice (n = 7–11 independent experiments). (E) Kaplan–Meier survival curve of csArnt–/– (n = 35) and csArnt–/– Ppara–/– double-knockout mice (n = 44) mice. There is a significant difference between the 2 curves based on log-rank analysis. (F) Schematic model for ARNT regulation of cardiac FA metabolism. Data are presented as the mean ± SEM. *P < 0.01.