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BMC Med Genomics. 2014 Jun 17;7:35. doi: 10.1186/1755-8794-7-35.

A systems biology approach to understand the pathophysiological mechanisms of cardiac pathological hypertrophy associated with rosiglitazone.

Author information

1
TNO, Department Microbiology and Systems Biology, P,O, Box 360, 3704 AJ Zeist, The Netherlands. Lars.Verschuren@tno.nl.

Abstract

BACKGROUND:

Cardiac pathological hypertrophy is associated with a significantly increased risk of coronary heart disease and has been observed in diabetic patients treated with rosiglitazone whereas most published studies do not suggest a similar increase in risk of cardiovascular events in pioglitazone-treated diabetic subjects. This study sought to understand the pathophysiological and molecular mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone and yield knowledge as to the causative nature of rosiglitazone-associated cardiac hypertrophy.

METHODS:

We used a high-fat diet-induced pre-diabetic mouse model to allow bioinformatics analysis of the transcriptome of the heart of mice treated with rosiglitazone or pioglitazone.

RESULTS:

Our data show that rosiglitazone and pioglitazone both markedly improved systemic markers for glucose homeostasis, fasting plasma glucose and insulin, and the urinary excretion of albumin. Only rosiglitazone, but not pioglitazone, tended to increase atherosclerosis and induced pathological cardiac hypertrophy, based on a significant increase in heart weight and increased expression of the validated markers, ANP and BNP. Functional enrichment analysis of the rosiglitazone-specific cardiac gene expression suggests that a shift in cardiac energy metabolism, in particular decreased fatty acid oxidation toward increased glucose utilization as indicated by down regulation of relevant PPARα and PGC1α target genes. This underlies the rosiglitazone-associated pathological hypertrophic cardiac phenotype in the current study.

CONCLUSION:

Application of a systems biology approach uncovered a shift in energy metabolism by rosiglitazone that may impact cardiac pathological hypertrophy.

PMID:
24938300
PMCID:
PMC4072889
DOI:
10.1186/1755-8794-7-35
[Indexed for MEDLINE]
Free PMC Article

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