Unknown,Transcriptomics,Genomics,Proteomics

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Systems biology analysis unravels complementary action of combined Rosuvastatin and Ezetimibe therapy

ABSTRACT: Transcriptomics analysis to understand both efficacy and side effects of a cholesterol lowering drug combination therapy based on biological pathways and molecular processes affected by each drug alone or in combination. We have treated ApoE*3Leiden mice, a humanized atherosclerosis model with a unique human-like response to cholesterol-lowering drugs, with RSV and EZE alone and in combination. We demonstrate that processes affected by monotherapy can be retained and enhanced by combination therapy. In addition, combination therapy also affects a number of processes which are not predictable on basis of monotherapy M-bM-^@M-^S at least when analysis is performed within the borders of statistical significance. Our data however provide clues for these M-bM-^@M-^\non-predictableM-bM-^@M-^] effects. Total RNA obtained from mouse liver from mice treated with High-Cholesterol (HC) diet as control (n=8) or HC+RSV (n=8) or HC+EZE (n=8) or HC+RSV+EZE (n=8).

ORGANISM(S): Mus musculus

SUBMITTER: Lars Verschuren

PROVIDER: E-GEOD-38688 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Systems biology analysis unravels the complementary action of combined rosuvastatin and ezetimibe therapy.

Verschuren Lars L Radonjic Marijana M Wielinga Peter Y PY Kelder Thomas T Kooistra Teake T van Ommen Ben B Kleemann Robert R

Pharmacogenetics and genomics 20121201 12

<h4>Aims</h4>Combination-drug therapy takes advantage of the complementary action of their individual components, thereby potentiating its therapeutic effect. Potential disadvantages include side effects that are not foreseen on basis of the data available from drug monotherapy. Here, we used a systems biology approach to understand both the efficacy and the side effects of a cholesterol-lowering drug-combination therapy on the basis of the biological pathways and molecular processes affected by ...[more]

PMID: 23086299

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Project description:HuntingtonM-bM-^@M-^Ys disease (HD) is a neurodegenerative disorder that is associated with the deposition of proteinaceous aggregates in the brains of HD patients and mouse models. Previous studies have suggested that wide-scale disruption of protein homeostasis occurs in protein folding diseases. Protein homeostasis can be maintained by activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1), the pharmacological activation of which can be achieved by Hsp90 inhibition and has been demonstrated to be beneficial in cell and invertebrate models of HD. Whether the HSR is functional in HD and whether its activation has therapeutic potential in mammalian HD models is currently unknown. To address these issues, we used a novel, brain penetrant Hsp90 inhibitor to activate the HSR in brain after systemic administration. Microarrays, quantitative PCR and western blotting showed that the HSR becomes impaired with disease progression in two mouse models of HD and that this originates at the level of transcription. HuntingtonM-bM-^@M-^Ys disease (HD) is a neurodegenerative disorder that is associated with the deposition of proteinaceous aggregates in the brains of HD patients and mouse models. Previous studies have suggested that wide-scale disruption of protein homeostasis occurs in protein folding diseases. Protein homeostasis can be maintained by activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1), the pharmacological activation of which can be achieved by Hsp90 inhibition and has been demonstrated to be beneficial in cell and invertebrate models of HD. Whether the HSR is functional in HD and whether its activation has therapeutic potential in mammalian HD models is currently unknown. To address these issues, we used a novel, brain penetrant Hsp90 inhibitor to activate the HSR in brain after systemic administration. Microarrays, quantitative PCR and western blotting showed that the HSR becomes impaired with disease progression in two mouse models of HD and that this originates at the level of transcription. mRNA expression analysis was performed by microarray in 12 week old R6/2 and WT mice treated with vehicle or HSP990 for 4h (12mg/kg).The following number of replicates was analysed for each genotype: 7 for WT+vehicle, 10 for WT+HSP990, 7 for R6/2+vehicle and 8 for R6/2+HSP990. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

Dataset Information

Systems biology analysis unravels complementary action of combined Rosuvastatin and Ezetimibe therapy

Publications

Systems biology analysis unravels the complementary action of combined rosuvastatin and ezetimibe therapy.

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