Abstract 223: Zinc-finger Nuclease Knockout Of Dual-specificity Protein Phosphatase-5 Enhances Myogenic Response In Autoregulation Of Cerebral Blood Flow In Fhh.1bn Rats

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Aron M Geurts ◽  
Mallikarjuna R Pabbidi ◽  
David R Harder ◽  
Howard Jacob ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Protein Phosphatase ◽  
Genetic Background ◽  
Zinc Finger Nuclease ◽  
Brown Norway ◽  
Myogenic Response ◽  
Protein Phosphatase 5 ◽  
Dual Specificity ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein

We recently reported that the pressure-induced myogenic responses of afferent arteries (Af-Art) and middle cerebral arteries (MCAs) were impaired in the fawn hooded hypertensive (FHH) rats and were restored in FHH.1BN congenic strain in which chromosome 1 from the Brown Norway (BN) rats containing 11 genes including dual-specificity protein phosphatase-5 (Dusp5) was transferred into FHH genetic background. There are 4 single nucleotide polymorphisms (SNP) in Dusp5 in FHH as compared with BN rats, one of which causes G155R mutation. To determine whether Dusp5 contributes to the impaired vascular myogenic response in FHH rats, we created a Dusp5 knockout (KO) rats in the FHH.1BN genetic background using zinc-finger nuclease (ZFN) that introduced a premature stop codon at amino acid (AA) 121. The expression of Dusp5 in KO rats were significantly decreased and the level of phosphorylated ERK2 (p-ERK2) was significantly increased in multiple organs including liver, spleen and white blood cells (WBCs). The luminal diameter of the MCAs in FHH.1BN rats (n=12) decreased 20 ± 2 % when the perfusion pressure was increased from 40 to 140 mmHg, whereas it decreased 34 ± 7 % in Dusp5 KO rats (n=6) and increased 10 ± 4% in FHH strain (n=8). Autoregulation was markedly impaired and CBF increased by 54 ± 6% in FHH rats when MAP was increased from 100 to 160 mmHg. CBF was better autoregulated in FHH.1BN strain and Dusp5 KO rats increased by only 26 ± 3% and 12 ± 3% when MAP was increased over the same range. However, the range of autoregulation of CBF was extended in the FHH rats (n=7) in that CBF rose to 107 ± 6% in FHH.1BN rats (n=7) when pressure was increased to 190 mmHg versus 33 ± 4% in the Dusp5 KO animals (n=6). These results suggest that Dusp5 plays an important role in modulating of myogenic tone in the cerebral circulation. Unless the G155R mutation activates Dusp5 in FHH rats, it is unlikely that Dusp5 is responsible for the impaired myogenic response in FHH rats.

scholarly journals Role of dual-specificity protein phosphatase-5 in modulating the myogenic response in rat cerebral arteries

2013 ◽  
Vol 114 (2) ◽  
pp. 252-261 ◽  
Author(s):  
Nadi T. Wickramasekera ◽  
Debebe Gebremedhin ◽  
Koryn A. Carver ◽  
Padmanabhan Vakeel ◽  
Ramani Ramchandran ◽  
...  
Keyword(s):  
Protein Expression ◽  
Protein Phosphatase ◽  
Single Channel ◽  
Cerebral Arteries ◽  
Protein Phosphatase 5 ◽  
Dual Specificity ◽  
Arterial Constriction ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein

The present study examined the role of the dual-specificity protein phosphatase-5 (DUSP-5) in the pressure-induced myogenic responses of organ-cultured cerebral arterial segments. In these studies, we initially compared freshly isolated and organ-cultured cerebral arterial segments with respect to responses to step increases in intravascular pressure, vasodilator and vasoconstrictor stimuli, activities of the large-conductance arterial Ca2+-activated K+ (KCa) single-channel current, and stable protein expression of DUSP-5 enzyme. The results demonstrate maintained pressure-dependent myogenic vasoconstriction, DUSP-5 protein expression, endothelium-dependent and -independent dilations, agonist-induced constriction, and unitary KCa channel conductance in organ-cultured cerebral arterial segments similar to that in freshly isolated cerebral arteries. Furthermore, using a permeabilization transfection technique in organ-cultured cerebral arterial segments, gene-specific small interfering RNA (siRNA) induced knockdown of DUSP-5 mRNA and protein, which were associated with enhanced pressure-dependent cerebral arterial myogenic constriction and increased phosphorylation of PKC-βII. In addition, siRNA knockdown of DUSP-5 reduced levels of phosphorylated ROCK and ERK1 with no change in the level of phosphorylated ERK2. Pharmacological inhibition of ERK1/2 phosphorylation significantly attenuated pressure-induced myogenic constriction in cerebral arteries. The findings within the present studies illustrate that DUSP-5, native in cerebral arterial muscle cells, appears to regulate signaling of pressure-dependent myogenic cerebral arterial constriction, which is crucial for the maintenance of constant cerebral blood flow to the brain.

scholarly journals Genome-scale comparative analysis for host resistance against sea lice between Atlantic salmon and rainbow trout

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pablo Cáceres ◽  
Agustín Barría ◽  
Kris A. Christensen ◽  
Liane N. Bassini ◽  
Katharina Correa ◽  
...  
Keyword(s):  
Rainbow Trout ◽  
Atlantic Salmon ◽  
Candidate Genes ◽  
Protein Phosphatase ◽  
Sea Lice ◽  
Genome Wide Association Studies ◽  
Dual Specificity ◽  
Dual Specificity Protein Phosphatase ◽  
Genomic Regions ◽  
Specificity Protein

AbstractSea lice (Caligus rogercresseyi) is an ectoparasite which causes major production losses in the salmon aquaculture industry worldwide. Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) are two of the most susceptible salmonid species to sea lice infestation. The objectives of this study were to: (1) identify genomic regions associated with resistance to Caligus rogercresseyi in Atlantic salmon and rainbow trout by performing single-step Genome-Wide Association studies (ssGWAS), and (2) identify candidate genes related to trait variation based on exploring orthologous genes within the associated regions across species. A total of 2626 Atlantic salmon and 2643 rainbow trout were challenged and genotyped with 50 K and 57 K SNP panels, respectively. We ran two independent ssGWAS for sea lice resistance on each species and identified 7 and 13 regions explaining more than 1% of the genetic variance for the trait, with the most important regions explaining 3% and 2.7% for Atlantic salmon and rainbow trout, respectively. We identified genes associated with immune response, cytoskeleton function, and cell migration when focusing on important genomic regions for each species. Moreover, we found 15 common orthogroups which were present in more than one associated genomic region, within- or between-species; however, only one orthogroup showed a clear potential biological relevance in the response against sea lice. For instance, dual-specificity protein phosphatase 10-like (dusp10) and dual-specificity protein phosphatase 8 (dusp8) were found in genomic regions associated with lice density in Atlantic salmon and rainbow trout, respectively. Dusp10 and dusp8 are modulators of the MAPK pathway and might be involved in the differences of the inflammation response between lice resistant and susceptible fish from both species. Our results provide further knowledge on candidate genes related to sea lice resistance and may help establish better control for sea lice in fish populations.

Sign in / Sign up

Export Citation Format

Share Document