PMID- 11834720
OWN - NLM
STAT- MEDLINE
DCOM- 20020221
LR  - 20211203
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 90
IP  - 2
DP  - 2002 Feb 8
TI  - Early expression of myocardial HIF-1alpha in response to mechanical stresses: 
      regulation by stretch-activated channels and the phosphatidylinositol 3-kinase 
      signaling pathway.
PG  - E25-33
AB  - Vascular endothelial growth factor (VEGF) expression is upregulated by 
      hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. 
      Normally, HIF-1 activity depends on the amount of HIF-1alpha subunit, which is 
      tightly regulated by the oxygen tension. In the myocardium, VEGF expression has 
      been shown to be induced under nonhypoxic conditions by mechanical stresses. 
      However, the cellular mechanism of stress-mediated VEGF induction remains 
      unclear. Therefore, we examined the possible involvement of HIF-1 in 
      stress-mediated VEGF induction in rat hearts. In this study, we increased the 
      left ventricular wall tension using 3 different methods, namely by inducing 
      regional ischemia, by expanding an intraventricular balloon, and by producing 
      hemodynamic overload using an aortocaval shunt. In all cases, HIF-1alpha 
      accumulated in the nuclei of cardiac myocytes in the early phase, and this was 
      followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt 
      phosphorylation was found to be activated by mechanical stress and completely 
      blocked by wortmannin (a PI3K inhibitor). Moreover, the stress-mediated induction 
      of HIF-1alpha and VEGF was suppressed by gadolinium (a stretch-activated channel 
      inhibitor), wortmannin, and rapamycin (a FRAP inhibitor). Our results suggest 
      that HIF-1alpha plays an important role in the induction of VEGF in nonischemic 
      and mechanically stressed myocardium, and that this is regulated by 
      stretch-activated channels and the PI3K/Akt/FRAP pathway. Moreover, this 
      signaling pathway, which induces HIF-1alpha, seems to play an important role in 
      the adaptation of the myocardium to stresses. The full text of this article is 
      available at http://www.circresaha.org.
FAU - Kim, Chan-Hyung
AU  - Kim CH
AD  - Department of Pharmacology and Heart Research Institute, BK21 Human Life 
      Sciences, Seoul National University College of Medicine, Chongno-gu, Seoul, 
      Korea.
FAU - Cho, Young-Suk
AU  - Cho YS
FAU - Chun, Yang-Sook
AU  - Chun YS
FAU - Park, Jong-Wan
AU  - Park JW
FAU - Kim, Myung-Suk
AU  - Kim MS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Androstadienes)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Ion Channels)
RN  - 0 (Lymphokines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - AU0V1LM3JT (Gadolinium)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Cell Nucleus/metabolism
MH  - Endothelial Growth Factors/genetics/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Gadolinium/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - In Vitro Techniques
MH  - Ion Channels/*metabolism
MH  - Lymphokines/genetics/metabolism
MH  - Male
MH  - Myocardial Ischemia/metabolism
MH  - Myocardium/cytology/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/pharmacology
MH  - Specific Pathogen-Free Organisms
MH  - Stress, Mechanical
MH  - Transcription Factors/*biosynthesis/genetics
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
MH  - Ventricular Function, Left/physiology
MH  - Wortmannin
EDAT- 2002/02/09 10:00
MHDA- 2002/02/22 10:01
CRDT- 2002/02/09 10:00
PHST- 2002/02/09 10:00 [pubmed]
PHST- 2002/02/22 10:01 [medline]
PHST- 2002/02/09 10:00 [entrez]
AID - 10.1161/hh0202.104923 [doi]
PST - ppublish
SO  - Circ Res. 2002 Feb 8;90(2):E25-33. doi: 10.1161/hh0202.104923.