Jie Li1, Guihua Yue1,2, Wenxia Ma1, Aizhen Zhang1,3, Jianqiu Zou1, Yafei Cai4, Xiaoli Tang5, Jun Wang6, Jinbao Liu7, Honglin Li8, Huabo Su1,9,7. 1. Vascular Biology Center (J.L., G.Y., W.M., A.Z., J.Z., H.S.), Medical College of Georgia, Augusta University. 2. Guangxi Medical College, Nanning, China (G.Y.). 3. Affiliated Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning (A.Z.). 4. College of Animal Science and Technology, Nanjing Agricultural University, China (Y.C.). 5. Department of Biochemistry, School of Medicine, Nanchang University, Jiangxi, China (X.T.). 6. Department of Basic Research Laboratories, Center for Stem Cell Engineering, Texas Heart Institute, Houston (J.W.). 7. Protein Modification and Degradation Lab, School of Basic Medical Sciences, Guangzhou Medical University, China (J.L., H.S.). 8. Department of Biochemistry and Molecular Biology (H.L.), Medical College of Georgia, Augusta University. 9. Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Augusta University.
Abstract
BACKGROUND: Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)-a novel ubiquitin-like protein-has not been explored in either the normal or stressed heart. METHODS AND RESULTS: Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)-an enzyme essential for Ufm1 modification-was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction. CONCLUSIONS: Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.
BACKGROUND: Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)-a novel ubiquitin-like protein-has not been explored in either the normal or stressed heart. METHODS AND RESULTS: Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)-an enzyme essential for Ufm1 modification-was increased in hypertrophicmouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction. CONCLUSIONS: Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.
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