RGD Reference Report - Zinc-finger nuclease knockout of dual-specificity protein phosphatase-5 enhances the myogenic response and autoregulation of cerebral blood flow in FHH.1BN rats.

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Zinc-finger nuclease knockout of dual-specificity protein phosphatase-5 enhances the myogenic response and autoregulation of cerebral blood flow in FHH.1BN rats.
Authors:	Fan, Fan Geurts, Aron M Pabbidi, Mallikarjuna R Smith, Stanley V Harder, David R Jacob, Howard Roman, Richard J
Citation:	Fan F, etal., PLoS One. 2014 Nov 14;9(11):e112878. doi: 10.1371/journal.pone.0112878. eCollection 2014.
RGD ID:	13446412
Pubmed:	PMID:25397684 (View Abstract at PubMed)
PMCID:	PMC4232417 (View Article at PubMed Central)
DOI:	DOI:10.1371/journal.pone.0112878 (Journal Full-text)
We recently reported that the myogenic responses of the renal afferent arteriole (Af-Art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow (RBF and CBF) were impaired in Fawn Hooded hypertensive (FHH) rats and were restored in a FHH.1BN congenic strain in which a small segment of chromosome 1 from the Brown Norway (BN) containing 15 genes including dual-specificity protein phosphatase-5 (Dusp5) were transferred into the FHH genetic background. We identified 4 single nucleotide polymorphisms in the Dusp5 gene in FHH as compared with BN rats, two of which altered CpG sites and another that caused a G155R mutation. To determine whether Dusp5 contributes to the impaired myogenic response in FHH rats, we created a Dusp5 knockout (KO) rat in the FHH.1BN genetic background using a zinc-finger nuclease that introduced an 11 bp frame-shift deletion and a premature stop codon at AA121. The expression of Dusp5 was decreased and the levels of its substrates, phosphorylated ERK1/2 (p-ERK1/2), were enhanced in the KO rats. The diameter of the MCA decreased to a greater extent in Dusp5 KO rats than in FHH.1BN and FHH rats when the perfusion pressure was increased from 40 to 140 mmHg. CBF increased markedly in FHH rats when MAP was increased from 100 to 160 mmHg, and CBF was better autoregulated in the Dusp5 KO and FHH.1BN rats. The expression of Dusp5 was higher at the mRNA level but not at the protein level and the levels of p-ERK1/2 and p-PKC were lower in cerebral microvessels and brain tissue isolated from FHH than in FHH.1BN rats. These results indicate that Dusp5 modulates myogenic reactivity in the cerebral circulation and support the view that a mutation in Dusp5 may enhance Dusp5 activity and contribute to the impaired myogenic response in FHH rats.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Dusp5	Rat	negative regulation of vasoconstriction		IMP			RGD
Dusp5	Rat	positive regulation of cerebral blood circulation		IMP			RGD

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Mammalian Phenotype

Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
FHH-Chr 1^BN/Mcwi	Rat	decreased cerebral blood flow rate	induced	IMP	controlled ex vivo artery perfusion pressure	compared to FHH.1BN	RGD
Dusp5	Rat	decreased vasoconstriction		IMP		compared to FHH.1BN	RGD
Dusp5^em1Mcwi	Rat	decreased vasoconstriction		IMP		compared to FHH.1BN	RGD
FHH-Chr 1^BN-Dusp5^em1Mcwi	Rat	decreased vasoconstriction	induced	IMP	controlled ex vivo artery perfusion pressure	compared to FHH.1BN	RGD
FHH	Rat	increased cerebral blood flow rate	induced	IMP	controlled ex vivo artery perfusion pressure	compared to FHH.1BN and SD	RGD
FHH	Rat	increased vasoconstriction	induced	IMP	controlled ex vivo artery perfusion pressure	compared to FHH.1BN and SD	RGD

Objects Annotated

Genes (Rattus norvegicus)

Dusp5 (dual specificity phosphatase 5)

Dusp5^em1Mcwi (dual specificity phosphatase 5; ZFN induced mutant1, Mcwi)

Strains

FHH (Fawn Hooded Hypertensive)

FHH-Chr 1^BN-Dusp5^em1Mcwi (NA)

FHH-Chr 1^BN/Mcwi (NA)

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Zinc-finger nuclease knockout of dual-specificity protein phosphatase-5 enhances the myogenic response and autoregulation of cerebral blood flow in FHH.1BN rats.

Mammalian Phenotype