Unknown,Transcriptomics,Genomics,Proteomics

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Downregulation of Plzf gene ameliorates metabolic and cardiac traits in the spontaneously hypertensive rat.

ABSTRACT: The spontaneously hypertensive rat (SHR) is the most widely used model of essential hypertension and is predisposed to left ventricular hypertrophy, myocardial fibrosis, and metabolic disturbances. Recently, a quantitative trait locus (QTL) influencing blood pressure, left ventricular mass and heart interstitial fibrosis was genetically isolated within 788 kb on chromosome 8 segment of SHR-PD5 congenic strain that contains only 7 genes, including mutant Plzf (promyelocytic leukemia zinc finger) gene. To identify Plzf as a quantitative trait gene, we targeted Plzf in the SHR using the TALEN technique and obtained SHR line harboring mutant Plzf gene with a premature stop codon at position of amino acid 58. The Plzf mutant allele is semi-lethal since approximately 95% of newborn homozygous animals die perinatally due to multiple developmental abnormalities. Heterozygous rats were grossly normal and were used for metabolic and hemodynamic analyses. SHR-Plzf+/- heterozygotes versus SHR wild type controls exhibited reduced body weight and relative weight of epididymal fat, lower serum and liver triglycerides and cholesterol and better glucose tolerance. In addition, SHR-Plzf+/- rats exhibited significantly increased sensitivity of adipose and muscle tissue to insulin action when compared to wild type controls. Blood pressure was comparable in SHR versus SHR-Plzf+/-, however, there was significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis in SHR-Plzf+/- rats. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes playing a role in metabolic pathways, PPAR signaling, and cell cycle regulation. These results provide evidence for an important role of Plzf in regulation of metabolic and cardiac traits in the rat and suggest a cross-talk between cell cycle regulators, metabolism, cardiac hypertrophy and fibrosis.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Vladimir Landa

PROVIDER: E-MTAB-3831 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Metabolic syndrome is associated with chronic low-grade inflammation which plays an important role in the pathogenesis of insulin resistance. Salsalate is a non-steroidal anti-inflammatory drug that reduces levels of inflammatory mediators. In the current study, we tested the effects of salsalate on inflammation, oxidative stress and metabolic disturbances in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 15-month-old male transgenic SHR-CRP rats with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without salsalate. In a similar fashion, we studied a group of nontransgenic SHR treated with salsalate and an untreated group of nontransgenic SHR controls. Parameters of inflammation and glucose and lipid metabolism were measured using standard methods. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that salsalate treatment decreased circulating levels of inflammatory markers TNFï¡ and MCP-1 and levels of human CRP as well as reduced levels of lipopreroxidation products in the liver and kidney cortex. Lipidomics analysis of eicosanoids confirmed anti-inflammatory effects of salsalate. Reduced inflammation and oxidative stress were associated with increased sensitivity of skeletal muscles to insulin action and greater tolerance to glucose and with reduced glucose oxidation and incorporation in brown adipose tissue (BAT). In SHR controls with no CRP-induced inflammation, salsalate treatment was associated with reduced body weight, lower levels of serum free fatty acids, total and HDL cholesterol and increased palmitate oxidation and incorporation in BAT. Salsalate regulated lipid metabolism by affecting expression of genes from PPAR signaling pathways and inflammation by affecting expression from MAPK signaling and NOD-like receptor signaling pathways. In summary, in the presence of high levels of human CRP, salsalate reduced inflammation which was associated with reduced oxidative stress and amelioration of insulin resistance in skeletal muscle and glucose intolerance while in non-transgenic SHR rats, salsalate ameliorated dyslipidemia and activated BAT. Thus it is possible that amelioration of insulin resistance and glucose intolerance in SHR-CRP rats treated with salsalate is due to reduced inflammation while amelioration of dyslipidemia in SHR rats treated with salsalate is due to activation of BAT. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

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Downregulation of Plzf gene ameliorates metabolic and cardiac traits in the spontaneously hypertensive rat.

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