Pharmacogenomic analysis of retinoic-acid induced dyslipidemia in congenic rat model

Krupková, Michaela; Liška, František; Šedová, Lucie; Křenová, D; Křen, Vladimı́r; Šeda, Ondřej

doi:10.1186/1476-511x-13-172

Cited by 8 publications

(3 citation statements)

References 39 publications

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“…SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics to protect cells from doxorubicin‐mediated cell death (Samant et al ., ). SIRT3 is likely to affect a specific response to ATRA (Krupkova et al ., ). This possibility is interesting and warrants further investigation regarding ATRA‐regulated OPA1 deacetylation in our work.…”

Section: Discussionmentioning

confidence: 97%

All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

Yang

Luo

Chen

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEDoxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All-trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its protective effects on doxorubicin-induced cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and the underlying mechanisms. EXPERIMENTAL APPROACHESCellular viability assays, Western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity. KEY RESULTSATRA significantly inhibited doxorubicin-induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species generation and restored expression levels of mRNA and proteins in the phase II detoxifying enzyme system: nuclear factor-E2-related factor 2, manganese superoxide dismutase, haem oxygenase-1, and mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers and mitochondrial respiration capacity, biogenesis and dynamics). Both a ERK1/2 inhibitor (U0126) and ERK2 siRNA, but not ERK1 siRNA, abolished the protective effect of ATRA against doxorubicin-induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells. CONCLUSIONS AND IMPLICATIONSATRA protected cardiomyocytes against doxorubicin-induced toxicity, by activating the ERK2 pathway, without compromising its anticancer efficacy. Therefore, ATRA is a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity. AbbreviationsATRA, all-trans retinoic acid; Bcl-2, B-cell lymphoma 2; Bcl-xl, B-cell lymphoma-extra-large; BrdU, 5-bromo-2′-deoxyuridine; Dox, doxorubicin; Drp1, dynamin-related protein 1; FCCP, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; HO1, haem oxygenase-1; Mfn1, mitofusin 1; Mfn2, mitofusin 2; MMP, mitochondrial membrane potential; MnSOD, manganese superoxide dismutase; MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) Nrf2, nuclear factor-E2-related factor 2; OCR, oxygen consumption rate; OPA1, optic atrophy 1; RARα, retinoic acid receptor α; ROS, reactive oxygen species; TFAM, mitochondrial transcription factor A BJP British Journal of Pharmacology

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Section: Discussionmentioning

confidence: 97%

All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

Yang

Luo

Chen

et al. 2015

British J Pharmacology

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“…For transcriptomic data, after evaluation of hybridization, quality control, and the data normalization by robust multi-array analysis, gene expression was compared between the SHR and the SHR-Dca strains using PARTEK Genomics Suite 6.6 (Partek, Inc., Chesterfield, MO, USA). Transcripts found to be significantly differentially expressed by more than 1.2-fold between the two strains after multiple comparison adjustment using the false discovery rate method (FDR<0.05) were included in gene enrichment and pathway analyses, which were performed using Ingenuity Pathway Analysis software (application build 364062M, content version 26127183) as described previously (Krupkova et al 2014, Sedova et al 2012.…”

Section: Statistical and Pathway Analysesmentioning

confidence: 99%

Connexin 50 Mutation Lowers Blood Pressure in Spontaneously Hypertensive Rat

Šeda

Liška²,

Pravenec³

et al. 2017

Physiol Res

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We assessed the effect of the previously uncovered gap junction protein alpha 8 (Gja8) mutation present in spontaneously hypertensive rat – dominant cataract (SHR-Dca) strain on blood pressure, metabolic profile, and heart and renal transcriptomes. Adult, standard chow-fed male rats of SHR and SHR-Dca strains were used. We found a significant, consistent 10-15 mmHg decrease in both systolic and diastolic blood pressures in SHR-Dca compared with SHR (P<0.01 and P<0.05, respectively; repeated measures analysis of variance (ANOVA)). With immunohistochemistry, we were able to localize Gja8 in heart, kidney, aorta, liver, and lungs, mostly in endothelium; with no differences in expression between strains. SHR-Dca rats showed decreased body weight, high-density lipoprotein cholesterol concentrations and basal insulin sensitivity in muscle. There were 21 transcripts common to the sets of 303 transcripts in kidney and 487 in heart showing >1.2-fold difference in expression between SHR and SHR-Dca. Tumor necrosis factor was the most significant upstream regulator and glial cell-derived neurotrophic factor family ligand-receptor interactions was the common enriched and downregulated canonical pathway both in heart and kidney of SHR-Dca. The connexin 50 mutation L7Q lowers blood pressure in the SHR-Dca strain, decreases high-density lipoprotein cholesterol, and leads to substantial transcriptome changes in heart and kidney.

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“…In addition to its role in adipogenesis, control of hepatic gluconeogenesis ( Chen et al, 2014 ), and cardiac hypertrophy ( Liska et al, 2017 ), genetic variation in human ZBTB16 was associated with increased obesity parameters and higher total and LDL cholesterol ( Bendlova et al, 2017 ). We have previously shown that rats carrying specific Zbtb16 allele are particularly sensitive to HSD, glucocorticoids, and retinoic acid in terms of induction of metabolic dysfunction ( Krupkova et al, 2014 , 2018 ). Therefore, we hypothesized that maternal HSD intake during pregnancy and lactation would program the offspring to develop metabolic alterations in adulthood and that these effects may be, to a certain extent, modified by genetic variation in Zbtb16 .…”

Section: Introductionmentioning

confidence: 99%

Maternal High-Sucrose Diet Affects Phenotype Outcome in Adult Male Offspring: Role of Zbtb16

et al. 2020

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Overnutrition in pregnancy and lactation affects fetal and early postnatal development, which can result in metabolic disorders in adulthood. We tested a hypothesis that variation of the Zbtb16 gene, a significant energy metabolism regulator, modulates the effect of maternal high-sucrose diet (HSD) on metabolic and transcriptomic profiles of the offspring. We used the spontaneously hypertensive rat (SHR) strain and a minimal congenic rat strain SHR- Zbtb16 , carrying the Zbtb16 gene allele originating from the PD/Cub rat, a metabolic syndrome model. Sixteen-week-old SHR and SHR- Zbtb16 rat dams were fed either standard diet (control groups) or a high-sucrose diet (HSD, 70% calories as sucrose) during pregnancy and 4 weeks of lactation. In dams of both strains, we observed an HSD-induced increase of cholesterol and triacylglycerol concentrations in VLDL particles and a decrease of cholesterol and triacylglycerols content in medium to very small LDL particles. In male offspring, exposure to maternal HSD substantially increased brown fat weight in both strains, decreased triglycerides in LDL particles, and impaired glucose tolerance exclusively in SHR. The transcriptome assessment revealed networks of transcripts reflecting the shifts induced by maternal HSD with major nodes including mir-126, Hsd11b1 in the brown adipose tissue, Pcsk9, Nr0b2 in the liver and Hsd11b1, Slc2a4 in white adipose tissue. In summary, maternal HSD feeding during pregnancy and lactation affected brown fat deposition and lipid metabolism in adult male offspring and induced major transcriptome shifts in liver, white, and brown adipose tissues. The Zbtb16 variation present in the SHR- Zbtb16 led to several strain-specific effects of the maternal HSD, particularly the transcriptomic profile shifts of the adult male offspring.

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Pharmacogenomic analysis of retinoic-acid induced dyslipidemia in congenic rat model

Cited by 8 publications

References 39 publications

All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

Connexin 50 Mutation Lowers Blood Pressure in Spontaneously Hypertensive Rat

Maternal High-Sucrose Diet Affects Phenotype Outcome in Adult Male Offspring: Role of Zbtb16

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