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Microarray gene expression profiling of heart failure induced in apolipoprotein E-deficient mice by treatment with rosiglitazone

ABSTRACT: The anti-diabetic drug and agonist of the peroxisome proliferator-activated receptor gamma (Pparg), rosiglitazone, was recently withdrawn in many countries because the drug use was associated with an increased risk of heart failure. To investigate underlying pathomechanisms, we chose 6-month-old apolipoprotein E (apoE)-deficient mice, which are prone to atherosclerosis and insulin resistance, and thereby mimic the risk profile of patients with cardiovascular disease. After 8 weeks of rosiglitazone treatment (30 mg/kg/day), echocardiography and histology analyses demonstrated that rosiglitazone had induced heart failure with cardiac dilation. Concomitantly, cardiac lipid overload and lipid-induced cardiomyocyte death developed. The microarray gene expression study of heart tissue from rosiglitazone-treated apoE-deficient mice relative to untreated apoE-deficient mice and non-transgenic B6 mice identified cardiac Pparg-dependent lipid metabolism genes in rosiglitazone-treated mice, which seem to trigger a major heart failure promoting pathway. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) rosiglitazone-treated 8-month-old apolipoprotein (apoE)-deficient mice with symptoms of heart failure, (ii) untreated 8-month-old apoE-deficient mice, and (iii) age-matched, untreated, non-transgenic B6 control mice.

ORGANISM(S): Mus musculus

SUBMITTER: Ursula Quitterer

PROVIDER: E-GEOD-28031 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:AIM: To investigate the molecular, structural, and functional impact of aerosols from two heat-not-burn-based MRTPs, the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2, compared with that of cigarette mainstream smoke (CS) on the cardiovascular system of ApoE-/- mice. METHOD: Female ApoE-/- mice were exposed to aerosols from THS 2.2 and CHTP 1.2 or to CS from 3R4F for up to 6 months at matching nicotine concentrations. A cessation and a switching group (3 months exposure to 3R4F CS followed by filtered air or CHTP 1.2 for 3 months) were included. Cardiovascular effects were investigated using echocardiography, histopathology, immunohistochemistry, and transcriptomics. RESULTS: Continuous exposure to aerosols from CHTP 1.2 and THS 2.2 did not affect the atherosclerosis progression, heart function, left ventricular structure and cardiovascular transcriptome. Exposure to CS from 3R4F triggered atherosclerosis progression, reduced systolic ejection fraction and fractional shortening, caused heart left ventricle hypertrophy and initiated significant dysregulation in the transcriptomes of the heart ventricle and thoracic aorta. Importantly, smoking cessation and switching to CHTP 1.2 aerosol similarly improved the structural, functional, and molecular changes caused by 3R4F CS. CONCLUSION: Exposure to aerosols from CHTP 1.2 and THS 2.2 lacked most of the CS exposure-related functional, structural and molecular effects. Smoking cessation or switching to CHTP 1.2 aerosol caused a similar recovery from the 3R4F CS effect in the ApoE-/- model with no further acceleration of plaque progression beyond the aging-related rate.

2021-08-16 | E-MTAB-7981 | biostudies-arrayexpress

2021-08-16 | E-MTAB-7980 | biostudies-arrayexpress

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