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

Lars Verschuren,Teake Kooistra,Marijana Radonjic,Robert Kleemann,Thomas Kelder,Peter Y Wielinga,Ben van Ommen,Kanita Salic

doi:10.1186/1755-8794-7-35

Abstract

BackgroundCardiac 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.MethodsWe 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.ResultsOur 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.ConclusionApplication of a systems biology approach uncovered a shift in energy metabolism by rosiglitazone that may impact cardiac pathological hypertrophy.

Highlights

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
In a high-fat diet-inducible model of combined hyperglycemia and cardiovascular disease we found that rosiglitazone and pioglitazone are effective glucose lowering drugs which markedly improved systemic markers of glucose homeostasis, fasting plasma glucose and insulin, and the urinary excretion of albumin
Our study demonstrate that validated markers for pathological cardiac hypertrophy, ANP and BNP [23], were elevated by rosiglitazone but not by pioglitazone

Summary

Introduction

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. The TZDs, Despite their chemical and mechanistic similarities, there are large cohort studies suggesting that rosiglitazone causes heart failure to a greater extent than pioglitazone, yet provides no additional therapeutic benefit [2,4,5]. Insight into the regulatory mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone may have translational implications and yield knowledge as to the causative nature of TZD-associated cardiac events in man [6]

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Conclusion