Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury.
Mice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype c...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2012-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3260203?pdf=render |
id |
doaj-f2e0bab7c5f441909bee50af9cdfa3d1 |
---|---|
record_format |
Article |
spelling |
doaj-f2e0bab7c5f441909bee50af9cdfa3d12020-11-25T01:38:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e3012910.1371/journal.pone.0030129Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury.Laila ElsherifXuerong WangMilana GrachoffBeata M WolskaDavid L GeenenJohn P O'BryanMice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where α-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, α-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that α-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the α-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the α-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury.http://europepmc.org/articles/PMC3260203?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laila Elsherif Xuerong Wang Milana Grachoff Beata M Wolska David L Geenen John P O'Bryan |
spellingShingle |
Laila Elsherif Xuerong Wang Milana Grachoff Beata M Wolska David L Geenen John P O'Bryan Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. PLoS ONE |
author_facet |
Laila Elsherif Xuerong Wang Milana Grachoff Beata M Wolska David L Geenen John P O'Bryan |
author_sort |
Laila Elsherif |
title |
Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. |
title_short |
Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. |
title_full |
Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. |
title_fullStr |
Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. |
title_full_unstemmed |
Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. |
title_sort |
cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
Mice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where α-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, α-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that α-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the α-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the α-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury. |
url |
http://europepmc.org/articles/PMC3260203?pdf=render |
work_keys_str_mv |
AT lailaelsherif cardiacspecificexpressionofthetetracyclinetransactivatorconfersincreasedheartfunctionandsurvivalfollowingischemiareperfusioninjury AT xuerongwang cardiacspecificexpressionofthetetracyclinetransactivatorconfersincreasedheartfunctionandsurvivalfollowingischemiareperfusioninjury AT milanagrachoff cardiacspecificexpressionofthetetracyclinetransactivatorconfersincreasedheartfunctionandsurvivalfollowingischemiareperfusioninjury AT beatamwolska cardiacspecificexpressionofthetetracyclinetransactivatorconfersincreasedheartfunctionandsurvivalfollowingischemiareperfusioninjury AT davidlgeenen cardiacspecificexpressionofthetetracyclinetransactivatorconfersincreasedheartfunctionandsurvivalfollowingischemiareperfusioninjury AT johnpobryan cardiacspecificexpressionofthetetracyclinetransactivatorconfersincreasedheartfunctionandsurvivalfollowingischemiareperfusioninjury |
_version_ |
1725054773574500352 |