PMID- 21382378
OWN - NLM
STAT- MEDLINE
DCOM- 20110926
LR  - 20131121
IS  - 1095-8584 (Electronic)
IS  - 0022-2828 (Linking)
VI  - 50
IP  - 6
DP  - 2011 Jun
TI  - Hypoxia and HIF-1 suppress SERCA2a expression in embryonic cardiac myocytes 
      through two interdependent hypoxia response elements.
PG  - 1008-16
LID - 10.1016/j.yjmcc.2011.02.017 [doi]
AB  - Sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) is an essential component of 
      cardiomyocyte excitation-contraction (EC)-coupling. Suppression of SERCA2a 
      expression induces contractile dysfunction and has been reported in various forms 
      of ischemic cardiac disease as well as in hypobaric hypoxia. The present study 
      investigated whether SERCA2a expression is regulated by hypoxia in embryonic 
      mouse cardiomyocytes and explored the underlying mechanism. We show that in 
      cultured embryonic cardiomyocytes hypoxia (1% O(2)) induce time-dependent 
      downregulation of SERCA2a expression. This mechanism manifested as specific 
      changes in cardiac myocyte calcium signals induced by reduced expression and 
      activity of SERCA2a. Chemical activation of hypoxia-inducible factor-1 (HIF-1) by 
      DFO or overexpression of normoxia-stabile HIF-1alpha (HIF-1alpha/VP16) suppressed 
      endogenous SERCA2a expression as well as the activity of the 
      SERCA2a-promoter-luciferase reporter. Analysis of the SERCA2a promoter found two 
      putative HIF-1 binding HRE-sites. Site-specific promoter mutagenesis revealed 
      that co-operative HIF-1 binding to both of these hypoxia response elements on the 
      SERCA2a promoter is required for expressional suppression. This mechanism 
      establishes a link between oxygen supply and calcium activity in embryonic 
      cardiac myocytes that is exploited in cardiac development, and further may offer 
      a possible explanation for the functional depression of SERCA2a seen in ischemic 
      and hypoxic myocardium.
CI  - Copyright (c) 2011 Elsevier Ltd. All rights reserved.
FAU - Ronkainen, Veli-Pekka
AU  - Ronkainen VP
AD  - Department of Physiology, Institute of Biomedicine and Biocenter Oulu, University 
      of Oulu, FI-90014 Oulu, Finland.
FAU - Skoumal, Reka
AU  - Skoumal R
FAU - Tavi, Pasi
AU  - Tavi P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110305
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Herpes Simplex Virus Protein Vmw65)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - S88TT14065 (Oxygen)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Binding Sites/genetics
MH  - Calcium/metabolism
MH  - Cell Hypoxia
MH  - Cells, Cultured
MH  - Cytosol/metabolism
MH  - *Gene Expression Regulation, Developmental
MH  - Gene Order
MH  - Herpes Simplex Virus Protein Vmw65/genetics/metabolism
MH  - Hypoxia-Inducible Factor 1/genetics/*metabolism
MH  - Mice
MH  - Models, Biological
MH  - Myocytes, Cardiac/*enzymology
MH  - Oxygen/metabolism
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Transport
MH  - Response Elements/genetics/*physiology
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/*metabolism
MH  - Sequence Homology, Nucleic Acid
EDAT- 2011/03/09 06:00
MHDA- 2011/09/29 06:00
CRDT- 2011/03/09 06:00
PHST- 2010/11/01 00:00 [received]
PHST- 2011/02/14 00:00 [revised]
PHST- 2011/02/25 00:00 [accepted]
PHST- 2011/03/09 06:00 [entrez]
PHST- 2011/03/09 06:00 [pubmed]
PHST- 2011/09/29 06:00 [medline]
AID - S0022-2828(11)00094-0 [pii]
AID - 10.1016/j.yjmcc.2011.02.017 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2011 Jun;50(6):1008-16. doi: 10.1016/j.yjmcc.2011.02.017. 
      Epub 2011 Mar 5.