Research Papers: Pathology:
Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency
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Tsung-Hsien Chen1, Mei-Ru Chen1, Tzu-Yin Chen1, Tzu-Chin Wu1, Shan-Wen Liu1,2, Ching-Han Hsu2, Gan-Guang Liou3, Yu-Ying Kao4, Guo-Chung Dong1, Pao-Hsien Chu5, Jiunn-Wang Liao6 and Kurt Ming-Chao Lin1
1 Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
2 Institute of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
3 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
4 Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
5 Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
6 Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, Taiwan
Kurt Ming-Chao Lin, email:
Keywords: protein aggregation, cardiac hypertrophy, fibrosis, heart failure, proteasome, Pathology Section
Received: February 18, 2016 Accepted: July 22, 2016 Published: August 02, 2016
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.
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