Regulation of phosphatase and tensin homolog on chromosome 10 in response to Hypoxia

Jinqiao Qian, Shukuan Ling, Alexander C. Castillo, Bo Long, Yochai Birnbaum, Yumei Ye

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number9
DOIs
StatePublished - May 1 2012

Fingerprint

Activating Transcription Factor 2
Chromosomes, Human, Pair 10
Phosphoric Monoester Hydrolases
Cardiac Myocytes
Reperfusion Injury
Coronary Vessels
Phosphorylation
Forkhead Transcription Factors
Ventricular Remodeling
Coronary Occlusion
Caspases
Left Ventricular Function
Ligation
Myocardium
Cell Death
Up-Regulation
Down-Regulation
Ischemia
Myocardial Infarction
Apoptosis

Keywords

  • Activating transcription factor 2
  • Akt
  • FAS ligand
  • Forkhead box o 1
  • Infarct size
  • Ischemia
  • P38
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Regulation of phosphatase and tensin homolog on chromosome 10 in response to Hypoxia. / Qian, Jinqiao; Ling, Shukuan; Castillo, Alexander C.; Long, Bo; Birnbaum, Yochai; Ye, Yumei.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 9, 01.05.2012.

Research output: Contribution to journalArticle

Qian, Jinqiao ; Ling, Shukuan ; Castillo, Alexander C. ; Long, Bo ; Birnbaum, Yochai ; Ye, Yumei. / Regulation of phosphatase and tensin homolog on chromosome 10 in response to Hypoxia. In: American Journal of Physiology - Heart and Circulatory Physiology. 2012 ; Vol. 302, No. 9.
@article{173f4606dac547fa810a2c32d724ce86,
title = "Regulation of phosphatase and tensin homolog on chromosome 10 in response to Hypoxia",
abstract = "Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation.",
keywords = "Activating transcription factor 2, Akt, FAS ligand, Forkhead box o 1, Infarct size, Ischemia, P38, Reperfusion",
author = "Jinqiao Qian and Shukuan Ling and Castillo, {Alexander C.} and Bo Long and Yochai Birnbaum and Yumei Ye",
year = "2012",
month = "5",
day = "1",
doi = "10.1152/ajpheart.00929.2011",
language = "English (US)",
volume = "302",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "9",

}

TY - JOUR

T1 - Regulation of phosphatase and tensin homolog on chromosome 10 in response to Hypoxia

AU - Qian, Jinqiao

AU - Ling, Shukuan

AU - Castillo, Alexander C.

AU - Long, Bo

AU - Birnbaum, Yochai

AU - Ye, Yumei

PY - 2012/5/1

Y1 - 2012/5/1

N2 - Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation.

AB - Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation.

KW - Activating transcription factor 2

KW - Akt

KW - FAS ligand

KW - Forkhead box o 1

KW - Infarct size

KW - Ischemia

KW - P38

KW - Reperfusion

UR - http://www.scopus.com/inward/record.url?scp=84860505753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860505753&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00929.2011

DO - 10.1152/ajpheart.00929.2011

M3 - Article

C2 - 22367504

AN - SCOPUS:84860505753

VL - 302

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 9

ER -