PMID- 20671234
OWN - NLM
STAT- MEDLINE
DCOM- 20101022
LR  - 20191210
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 107
IP  - 7
DP  - 2010 Oct 1
TI  - Sphingosine-1-phosphate-dependent activation of p38 MAPK maintains elevated 
      peripheral resistance in heart failure through increased myogenic 
      vasoconstriction.
PG  - 923-33
LID - 10.1161/CIRCRESAHA.110.226464 [doi]
AB  - RATIONALE: Mechanisms underlying vasomotor abnormalities and increased peripheral 
      resistance exacerbating heart failure (HF) are poorly understood. OBJECTIVE: To 
      explore the role and molecular basis of myogenic responses in HF. METHODS AND 
      RESULTS: 10 weeks old C57Bl6 mice underwent experimental myocardial infarction 
      (MI) or sham surgery. At 1 to 12 weeks postoperative, mice underwent hemodynamic 
      studies, mesenteric, cerebral, and cremaster artery perfusion myography and 
      Western blot. Organ weights and hemodynamics confirmed HF and increased 
      peripheral resistance after MI. Myogenic responses, ie, pressure-induced 
      vasoconstriction, were increased as early as 1 week after MI and remained 
      elevated. Vasoconstrictor responses to phenylephrine were decreased 1 week after 
      MI, but not at 2 to 6 weeks after MI, whereas those to endothelin (ET)-1 and 
      sphingosine-1-phosphate (S1P) were increased at all time points after MI. An 
      antagonist (JTE-013) for the most abundant S1P receptor detected in mesenteric 
      arteries (S1P(2)R) abolished the enhanced myogenic responses of HF, with 
      significantly less effect on controls. Mice with genetic absence of 
      sphingosine-kinases or S1P(2)R (Sphk1(-/-); Sphk1(-/-)/Sphk2(+/-); S1P(2)R(-/-)) 
      did not manifest enhanced myogenic responses after MI. Mesenteric arteries from 
      HF mice exhibited increased phosphorylation of myosin light chain, with 
      deactivation of its phosphatase (MLCP). Among known S1P-responsive regulators of 
      MLCP, GTP-Rho levels were unexpectedly reduced in HF, whereas levels of activated 
      p38 MAPK and ERK1/2 (extracellular signal-regulated kinase 1/2) were increased. 
      Inhibiting p38 MAPK abolished the myogenic responses of animals with HF, with 
      little effect on controls. CONCLUSIONS: Rho-independent p38 MAPK-mediated 
      deactivation of MLCP underlies S1P/S1P(2)R-regulated increases in myogenic 
      vasoconstriction observed in HF. Therapeutic targeting of these findings in HF 
      models deserves study.
FAU - Hoefer, Judith
AU  - Hoefer J
AD  - Toronto General Hospital Research Institute, Toronto, ON, Canada.
FAU - Azam, M Ali
AU  - Azam MA
FAU - Kroetsch, Jeffrey T E
AU  - Kroetsch JT
FAU - Leong-Poi, Howard
AU  - Leong-Poi H
FAU - Momen, M Abdul
AU  - Momen MA
FAU - Voigtlaender-Bolz, Julia
AU  - Voigtlaender-Bolz J
FAU - Scherer, Elias Q
AU  - Scherer EQ
FAU - Meissner, Anja
AU  - Meissner A
FAU - Bolz, Steffen-Sebastian
AU  - Bolz SS
FAU - Husain, Mansoor
AU  - Husain M
LA  - eng
GR  - 53900/Canadian Institutes of Health Research/Canada
GR  - FRN 117801/Canadian Institutes of Health Research/Canada
GR  - MOP-84402/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100729
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Lysophospholipids)
RN  - 0 (Myosin Light Chains)
RN  - 0 (Receptors, Lysosphingolipid)
RN  - 0 (Sphingosine-1-Phosphate Receptors)
RN  - 0 (sphingosine-1-phosphate receptor-2, mouse)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Coronary Circulation/*physiology
MH  - Disease Models, Animal
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Heart Failure/metabolism/physiopathology
MH  - Lysophospholipids/*metabolism/pharmacology
MH  - MAP Kinase Signaling System/physiology
MH  - Male
MH  - Mesenteric Arteries/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscle, Skeletal/blood supply
MH  - Myocardial Infarction/metabolism/*physiopathology
MH  - Myosin Light Chains/metabolism
MH  - Receptors, Lysosphingolipid/genetics/metabolism
MH  - Sphingosine/*analogs & derivatives/metabolism/pharmacology
MH  - Sphingosine-1-Phosphate Receptors
MH  - Vascular Resistance/*physiology
MH  - Vasoconstriction/*physiology
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
EDAT- 2010/07/31 06:00
MHDA- 2010/10/23 06:00
CRDT- 2010/07/31 06:00
PHST- 2010/07/31 06:00 [entrez]
PHST- 2010/07/31 06:00 [pubmed]
PHST- 2010/10/23 06:00 [medline]
AID - CIRCRESAHA.110.226464 [pii]
AID - 10.1161/CIRCRESAHA.110.226464 [doi]
PST - ppublish
SO  - Circ Res. 2010 Oct 1;107(7):923-33. doi: 10.1161/CIRCRESAHA.110.226464. Epub 2010 
      Jul 29.