Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex
Hui-Hua Li, … , Da-Zhi Wang, Cam Patterson
Hui-Hua Li, … , Da-Zhi Wang, Cam Patterson
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1058-1071. https://doi.org/10.1172/JCI22220.
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Article Cardiology

Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex

Abstract

Calcineurin, which binds to the Z-disc in cardiomyocytes via α-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and α-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCFatrogin-1 complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCFatrogin-1 ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.

Authors

Hui-Hua Li, Vishram Kedar, Chunlian Zhang, Holly McDonough, Ranjana Arya, Da-Zhi Wang, Cam Patterson

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Figure 9

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Atrogin-1 blunts the hypertrophic response to pressure overload. (A) Rep...
Atrogin-1 blunts the hypertrophic response to pressure overload. (A) Representative heart sizes and heart weight/body weight ratios of atrogin-1 transgenic mice were compared with those of nontransgenic mice. Eight-week-old mice were subjected to thoracic aortic banding (TAB) or sham surgery. Fourteen days later, animals were sacrificed, the hearts were freshly isolated from transgenic (Tg) and nontransgenic (WT) mice, and heart weight/body weight ratios were determined (n = 7). Scale bar: 1 mm. (B) Representative macroscopic histologic analysis of H&E-stained hearts from indicated mice after 2 weeks of aortic banding is shown (top panels). Scale bar: 1 mm. Histologic sections were also stained with Masson’s trichrome to detect interstitial cell fibrosis in hearts (middle panels; magnification, ×200), and with wheat germ agglutinin–TRITC conjugate to determine cell size (bottom panels; scale bars: 50 μm). (C) Quantitation of myocyte cross-sectional areas from the indicated groups (n = 200 cells per section). (D) Analysis of hypertrophic markers. Total RNA was isolated from hearts of mice of the indicated genotype, and expression of transcripts for ANF, β-MHC, skeletal α-actin, and GAPDH was determined by slot blot analysis. A representative analysis is shown.