title: S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt.
abstract: 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.
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors: Ruomin
authors: R
authors: Di
authors: Xiangqi
authors: X
authors: Wu
authors: Zai
authors: Z
authors: Chang
authors: Xia
authors: X
authors: Zhao
authors: Qiuting
authors: Q
authors: Feng
authors: Shuangshuang
authors: S
authors: Lu
authors: Qing
authors: Q
authors: Luan
authors: Brian A
authors: BA
authors: Hemmings
authors: Xinli
authors: X
authors: Li
authors: Zhongzhou
authors: Z
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D017353:Gene Deletion; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D007093:Imidazoles; C552719:PF-4708671; C000631433:Pdk1 protein, mouse; D010879:Piperazines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus