title: Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency.
abstract: Proteinopathy in the heart which often manifests excessive misfolded/aggregated proteins in cardiac myocytes can result in severe fibrosis and heart failure. Here we developed a mouse model, which transgenically express tetrameric DsRed, a red fluorescent protein (RFP), in an attempt to mimic the pathological mechanisms ofcardiac fibrosis. Whilst DsRed is expressed and forms aggregation in most mouse organs, certain pathological defects are specifically recapitulated in cardiac muscle cells including mitochondria damages, aggresome-like residual bodies, excessive ubiquitinated proteins, and the induction of autophagy. The proteinopathy and cellular injuries caused by DsRed aggregates may be due to impaired or overburdened ubiquitin-proteasome system and autophagy-lysosome systems. We further identified that DsRed can be ubiquitinated and associated with MuRF1, a muscle-specific E3 ligase. Concomitantly, an activation of NF-κB signaling and a strong TIMP1 induction were noted, suggesting that RFP-induced fibrosis was augmented by a skewed balance between TIMP1 and MMPs. Taken together, our study highlights the molecular consequences of uncontrolled protein aggregation leading to congestive heart failure, and provides novel insights into fibrosis formation that can be exploited for improved therapy.
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Tsung-Hsien
authors: TH
authors: Chen
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Mei-Ru
authors: MR
authors: Chen
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Tzu-Yin
authors: TY
authors: Chen
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Tzu-Chin
authors: TC
authors: Wu
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.|Institute of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors: Shan-Wen
authors: SW
authors: Liu
authors: Institute of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors: Ching-Han
authors: CH
authors: Hsu
authors: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Gan-Guang
authors: GG
authors: Liou
authors: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors: Yu-Ying
authors: YY
authors: Kao
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Guo-Chung
authors: GC
authors: Dong
authors: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors: Pao-Hsien
authors: PH
authors: Chu
authors: Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, Taiwan.
authors: Jiunn-Wang
authors: JW
authors: Liao
authors: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors: Kurt Ming-Chao
authors: KM
authors: Lin
mesh_terms: D000818:Animals; D001343:Autophagy; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology; D008164:Luminescent Proteins / Q000737:chemistry*; D051379:Mice; D018482:Muscle, Skeletal / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D066329:Protein Aggregates; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D054875:Ubiquitination
chemical_list: D008164:Luminescent Proteins; D066329:Protein Aggregates; D019715:Tissue Inhibitor of Metalloproteinase-1; C413663:fluorescent protein 583; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: Pathology Section; cardiac hypertrophy; fibrosis; heart failure; proteasome; protein aggregation