PMID- 18660830
OWN - NLM
STAT- MEDLINE
DCOM- 20090220
LR  - 20211020
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 155
IP  - 6
DP  - 2008 Nov
TI  - Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human 
      vascular smooth muscle cells: inhibition with iloprost and NONOate.
PG  - 847-56
LID - 10.1038/bjp.2008.300 [doi]
AB  - BACKGROUND AND PURPOSE: To determine whether there is an association between 
      vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 
      (PDE5) in human vascular smooth muscle cell (hVSMCs). EXPERIMENTAL APPROACH: 
      hVSMCs were incubated with xanthine-xanthine oxidase (X-XO; a superoxide 
      generating system) or the thromboxane A(2) analogue, U46619 (+/-superoxide 
      dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was 
      assessed using Western blotting and superoxide measured. The role of Rac(1) in 
      superoxide generation was assessed by overexpressing either the dominant-negative 
      or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and 
      the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. 
      KEY RESULTS: Following 16 h incubation, U46619 and X-XO promoted the expression 
      of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over 
      the same time course. X-XO and U46619 both promoted the formation of superoxide. 
      Overexpression of dominant-negative Rac(1) or addition of iloprost, DETA-NONOate 
      or Y27632 completely blocked both superoxide release and PDE5 protein expression 
      and activity. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that 
      superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As 
      PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions 
      of NO.
FAU - Muzaffar, S
AU  - Muzaffar S
AD  - Bristol Heart Institute, University of Bristol, Bristol, UK. 
      s.muzaffar@bristol.ac.uk
FAU - Shukla, N
AU  - Shukla N
FAU - Bond, M
AU  - Bond M
FAU - Sala-Newby, G B
AU  - Sala-Newby GB
FAU - Newby, A C
AU  - Newby AC
FAU - Angelini, G D
AU  - Angelini GD
FAU - Jeremy, J Y
AU  - Jeremy JY
LA  - eng
GR  - SS/06/056/20884/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080728
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Nitric Oxide Donors)
RN  - 0 (Nitroso Compounds)
RN  - 0 (Phosphodiesterase 5 Inhibitors)
RN  - 0 (Vasodilator Agents)
RN  - 11062-77-4 (Superoxides)
RN  - 146724-94-9 (2,2'-(hydroxynitrosohydrazono)bis-ethanamine)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5)
RN  - JED5K35YGL (Iloprost)
SB  - IM
MH  - Cells, Cultured
MH  - Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism
MH  - Humans
MH  - Iloprost/*pharmacology
MH  - *Muscle, Smooth, Vascular/drug effects/enzymology/metabolism
MH  - NADPH Oxidases/*metabolism
MH  - Nitric Oxide Donors/pharmacology
MH  - Nitroso Compounds/*pharmacology
MH  - *Phosphodiesterase 5 Inhibitors
MH  - Saphenous Vein/cytology
MH  - Superoxides/*metabolism/pharmacology
MH  - Up-Regulation
MH  - Vasodilator Agents/pharmacology
PMC - PMC2597240
EDAT- 2008/07/29 09:00
MHDA- 2009/02/21 09:00
PMCR- 2009/11/01
CRDT- 2008/07/29 09:00
PHST- 2008/07/29 09:00 [pubmed]
PHST- 2009/02/21 09:00 [medline]
PHST- 2008/07/29 09:00 [entrez]
PHST- 2009/11/01 00:00 [pmc-release]
AID - bjp2008300 [pii]
AID - 10.1038/bjp.2008.300 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2008 Nov;155(6):847-56. doi: 10.1038/bjp.2008.300. Epub 2008 Jul 
      28.