Overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) contributes towards refractory hypotension, impaired microvascular perfusion and end organ damage in septic shock patients. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for BH4 biosynthesis. Under inflammatory conditions, GCH1 activity and hence BH4 levels are increased, supporting pathological NOS activity. GCH1 activity can be controlled through allosteric interactions with GCH1 feedback regulatory protein (GFRP). We investigated whether over expression of GFRP can regulate BH4 and NO production and attenuate cardiovascular dysfunction in sepsis.Sepsis was induced in mice conditionally over-expressing GFRP and wildtype littermates by caecal ligation and puncture. Blood pressure was monitored by radiotelemetry and mesenteric blood flow was quantified by laser speckle contrast imaging. Blood biochemistry data was obtained using an iSTAT analyser and BH4 levels were measured in plasma and tissues by HPLC.Increased BH4 and NO production and hypotension were observed in all mice but the extents of these pathophysiological changes were attenuated in GFRP OE mice. Perturbations in blood biochemistry were similarly attenuated in GFRP OE compared to WT controls. These results suggest that GFRP over-expression regulates GCH1 activity during septic shock, which in turn limits BH4 bioavailability for iNOS.We conclude that the GCH1-GFRP axis is a critical regulator of BH4 and NO production and the cardiovascular derangements that occur in septic shock.
Pharmacology, Toxicology and Pharmaceutical Science
1
4%
Biochemistry, Genetics and Molecular Biology
1
4%
Immunology and Microbiology
1
4%
Other
2
8%
Unknown
11
46%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 25 February 2015.
All research outputs
#15,184,741
of 25,394,764 outputs
Outputs from Shock
#1,191
of 3,260 outputs
Outputs of similar age
#134,411
of 268,152 outputs
Outputs of similar age from Shock
#8
of 45 outputs
Altmetric has tracked 25,394,764 research outputs across all sources so far. This one is in the 38th percentile – i.e., 38% of other outputs scored the same or lower than it.
So far Altmetric has tracked 3,260 research outputs from this source. They receive a mean Attention Score of 3.0. This one has gotten more attention than average, scoring higher than 61% of its peers.
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We're also able to compare this research output to 45 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 80% of its contemporaries.
