In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.
Skip Nav Destination
Article navigation
January 2012
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
December 14 2011
S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt
Ruomin Di;
Ruomin Di
1
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
†Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
‡Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
Search for other works by this author on:
Xiangqi Wu;
Xiangqi Wu
1
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
†Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Search for other works by this author on:
Zai Chang;
Zai Chang
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
Search for other works by this author on:
Xia Zhao;
Xia Zhao
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
Search for other works by this author on:
Qiuting Feng;
Qiuting Feng
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
†Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Search for other works by this author on:
Shuangshuang Lu;
Shuangshuang Lu
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
Search for other works by this author on:
Qing Luan;
Qing Luan
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
Search for other works by this author on:
Brian A. Hemmings;
Brian A. Hemmings
§Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
Search for other works by this author on:
Xinli Li;
Xinli Li
2
†Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Correspondence may be addressed to either of these authors (email zhongzhouyang@nju.edu.cn or xinli3267@yeah.net).
Search for other works by this author on:
Zhongzhou Yang
Zhongzhou Yang
2
*MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
2Correspondence may be addressed to either of these authors (email zhongzhouyang@nju.edu.cn or xinli3267@yeah.net).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
January 04 2011
Revision Received:
August 26 2011
Accepted:
September 09 2011
Accepted Manuscript online:
September 09 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 199–207.
Article history
Received:
January 04 2011
Revision Received:
August 26 2011
Accepted:
September 09 2011
Accepted Manuscript online:
September 09 2011
Citation
Ruomin Di, Xiangqi Wu, Zai Chang, Xia Zhao, Qiuting Feng, Shuangshuang Lu, Qing Luan, Brian A. Hemmings, Xinli Li, Zhongzhou Yang; S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt. Biochem J 1 January 2012; 441 (1): 199–207. doi: https://doi.org/10.1042/BJ20110033
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.