國家衛生研究院 NHRI:Item 3990099045/6691

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Title:	Transgenic expression of DsRed tetramers causes carditis and dilated heart failure
Authors:	Lin, K;Chen, MR;Wu, TC;Liu, SW;Hsu, CH
Contributors:	Division of Medical Engineering Research
Abstract:	Previously, the attempts to generate transgenic mice ubiquitously expressing tetrameric DsRed (a coral red fluorescent protein of Discosoma genus) were failed probably due to the toxicity of aggregated red fluorescent proteins in embryonic stem cells. Thus, the physiological outcome of expressing DsRed tetramers in adult mice was not explored. In this study we generated the transgenic red mouse by first generating a green to red switchable mouse with a vector containing loxP-EGFP-loxP cassette preceding the DsRed sequence, and the red mouse was resulted by cross the switchable mouse with a Cre mouse. The resulted mouse expressing DsRed tetramers was normal in development, size, and husbandry. However, mice with homozygous DsRed alleles developed respiratory distress, carditis, ventricular hypertrophy and fibrosis, left atrium thrombosis, dilated heart failure, and death at the age averaging 5.5 months old. The hemizygote mice developed similar symptoms at an average 12 months old. To confirm the heart origin of the morbidity in red mice, we induced DsRed expression specifically in cardiac tissues and the results confirmed the same diseased phenotypes by expressing DsRed only in the heart. To explore the cause of carditis and the underlying association with aggregated DsRed, we performed the molecular analysis on red mice at earlier stages and found that expression of myopathy and fibrosis related genes were significantly altered at 8 wk, long before the appearance of pathological abnormality and clinical onset of the diseases. Interestingly, expression of the proliferation and senescence related genes were also altered in cardiac tissues and in the primary skeletal myoblasts of the red mice. While the direct molecular evidence for the toxicity of tetrameric DsRed proteins remains unclear to us and that the red mice intriguingly managed the protein aggregates without symptoms until 5 months old, the transgenic mouse with DsRed expression can suffice a valuable in vivo model for failed protein quality control and can be utilized in the studies on protein aggregate toxicity and on the cardiac myopathy that relates to senescence and autophagy of myocytes. This research is supported by National Health Research Institutes, Taiwan, intramural grants.
Date:	2012-08
Relation:	Protein Science. 2012 Aug;21(S1):173-174.
Link to:	http://dx.doi.org/10.1002/pro.2113
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0961-8368&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000307019800305
Appears in Collections:	[Kurt Ming-Chao Lin] Conference Papers/Meeting Abstract

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