PMID- 17545479
OWN - NLM
STAT- MEDLINE
DCOM- 20071019
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 293
IP  - 3
DP  - 2007 Sep
TI  - Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing 
      attenuates acute inflammatory responses in postischemic myocardium.
PG  - H1571-80
AB  - Emerging research suggests that oxidant-driven transcription of key 
      cytokine/chemokine networks within the myocardium plays a crucial role in 
      producing ischemia-reperfusion (I/R) injury. We recently showed that activation 
      of hypoxia-inducible factor-1 (HIF-1) attenuated cardiac I/R injury. Diminished 
      injury in these prior studies was associated with significant reductions in 
      circulating interleukin-8 levels, suggesting that HIF-1 may play an important 
      role in modulating postischemic cardiac inflammation. In the current study, we 
      examined the role of HIF-1 activation in modulating proinflammatory chemokine 
      [macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil 
      chemoattractant factor (KC), and lipopolysaccharide-induced CXC chemokine (LIX)] 
      and adhesion molecule [intercellular adhesion molecule (ICAM)-1] expression in 
      murine cardiomyocytes in vitro (HL-1 cell line) and in intact murine hearts 
      following in vivo I/R injury. Our results show that HIF-1 activation induced both 
      pharmacologically by the prolyl hydroxylase inhibitor dimethyloxallyl glycine and 
      via small-interfering RNA (siRNA)-mediated prolyl-4 hydroxylase-2 (P4HA2) gene 
      silencing significantly attenuated tumor necrosis factor-alpha-induced chemokine 
      (KC and LIX) and ICAM-1 expression in cardiomyocytes. In vivo, postischemic 
      hearts obtained from animals receiving the P4HA2 siRNA (HIF-1 activation) 
      exhibited significantly reduced CXC chemokine (MIP-2, KC, and LIX), CC chemokine 
      (monocyte chemoattractant protein-1), and ICAM-1 expression when compared with 
      postischemic hearts from either saline I/R controls or postischemic hearts from 
      animals receiving a nontargeting control siRNA (no HIF-1 activation). Diminished 
      chemokine and adhesion molecule expression in HIF-1-activated postischemic hearts 
      was associated with significantly reduced polymorphonuclear leukocyte 
      infiltration and myocardial infarct size (>60% reduction P4HA2 siRNA I/R vs. 
      saline I/R, P < 0.001, n = 6). In conclusion, these results demonstrate for the 
      first time that HIF-1 activation following infusion of siRNA to P4HA2 plays a key 
      role in modulating I/R-associated cardiac inflammatory responses.
FAU - Natarajan, Ramesh
AU  - Natarajan R
AD  - Division of Pulmonary and Critical Care Medicine, Department of Internal 
      Medicine, Virginia Commonwealth University, PO Box 980050, Richmond, VA 
      23298-0050, USA.
FAU - Salloum, Fadi N
AU  - Salloum FN
FAU - Fisher, Bernard J
AU  - Fisher BJ
FAU - Ownby, Evan D
AU  - Ownby ED
FAU - Kukreja, Rakesh C
AU  - Kukreja RC
FAU - Fowler, Alpha A 3rd
AU  - Fowler AA 3rd
LA  - eng
GR  - 5P30NS-047463/NS/NINDS NIH HHS/United States
GR  - HL-059469/HL/NHLBI NIH HHS/United States
GR  - HL-076423/HL/NHLBI NIH HHS/United States
GR  - HL-51045/HL/NHLBI NIH HHS/United States
GR  - HL-79424/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070601
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Chemokine CXCL5)
RN  - 0 (Chemokines)
RN  - 0 (Chemokines, CXC)
RN  - 0 (Cxcl2 protein, mouse)
RN  - 0 (Cxcl5 protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Interleukin-8)
RN  - 0 (RNA, Small Interfering)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Chemokine CXCL2
MH  - Chemokine CXCL5
MH  - Chemokines/metabolism
MH  - Chemokines, CXC/metabolism
MH  - *Gene Silencing
MH  - Heme Oxygenase-1/metabolism
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - Interleukin-8/metabolism
MH  - Mice
MH  - Myocardial Infarction/pathology/prevention & control
MH  - Myocardial Reperfusion Injury/metabolism/*prevention & control
MH  - Myocardium/cytology/*metabolism
MH  - Myocytes, Cardiac/*metabolism
MH  - Nitric Oxide Synthase Type II/metabolism
MH  - Procollagen-Proline Dioxygenase/genetics/*metabolism
MH  - RNA, Small Interfering/pharmacology
EDAT- 2007/06/05 09:00
MHDA- 2007/10/20 09:00
CRDT- 2007/06/05 09:00
PHST- 2007/06/05 09:00 [pubmed]
PHST- 2007/10/20 09:00 [medline]
PHST- 2007/06/05 09:00 [entrez]
AID - 00291.2007 [pii]
AID - 10.1152/ajpheart.00291.2007 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1571-80. doi: 
      10.1152/ajpheart.00291.2007. Epub 2007 Jun 1.