Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Abstract

Peroxisome proliferator-activated receptor (PPAR)-␥ modulators, a class of antidiabetic drugs, have been associated with cardiovascular risks in type 2 diabetes in humans. The objective of this study was to explore possible cardiovascular risk biomarkers associated with PPAR-␥ in rodents that could provide an alert for risk to humans. Normal, myocardial infarction-induced heart failure (HF) or Zucker diabetic fatty (ZDF) rats were used. Rats (n ϭ 5-6) were treated with either vehicle or rosiglitazone (RGZ; 3 or 45 mg/kg/day p.o.) for 4 weeks. Biomarkers for potential cardiovascular risks were assessed, including 1) ultrasound for cardiac structure and function; 2) neuroendocrine and hormonal plasma biomarkers of cardiovascular risk; 3) pharmacogenomic profiling of cardiac and renal tissue by targeted tissue low-density gene array representing ion channels and transporters, and components of the renin-angiotensin-aldosterone system; and 4) immunohistochemistry for cardiac fibrosis, hypertrophy, and inflammation (macrophages and tumor necrosis factor-␣). HF was confirmed by increase in cardiac brain natriuretic peptide expression (p Ͻ 0.01) and echocardiography. Adequate exposure of RGZ was confirmed by pharmacokinetics (plasma drug levels) and the pharmacodynamic biomarker adiponectin. In normal or HF rats, RGZ had no negative effects on any of the biomarkers investigated. Similarly, RGZ had no significant effects on gene expression except for the increase in interleukin-6 mRNA expression in the heart and decrease in epithelial sodium channel ␤ in the kidney. In contrast, echocardiography showed improved cardiac structure and function after RGZ in ZDF rats. Taken together, this study suggests a limited predictive power of these preclinical models in respect to observed clinical adverse effects associated with RGZ.

Secreted Klotho and Chronic Kidney Disease

“…PPAR-gamma (PPAR-γ), also known as the glitazone receptor, is the molecular target of thiazolidinediones (TZDs), and has been used for treatment of Type II diabetes mellitus (DM) in human. 225 …”

Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet-Induced Obesity

“…A higher dose (6 mg/kg) was also tested, because 3 mg/kg failed to completely normalize insulin sensitivity. It is noteworthy that rosiglitazone exhibits first-order kinetics in rats, such that a doubling of the dose yields a doubling of plasma levels (Wang et al, 2010;Gao and Jusko, 2012 Surgery. After ϳ3.5 weeks on the diets, rats were weighed and anesthetized with 2% isoflurane in 100% oxygen.…”

“…The lower dose of rosiglitazone (3 mg/kg) was chosen, because it is a frequently used efficacious dose in rats ( Törü ner et al, 2004;Khan et al, 2005;Moore et al, 2008;Wang et al, 2010). A higher dose (6 mg/kg) was also tested, because 3 mg/kg failed to completely normalize insulin sensitivity.…”

Pharmacogenomics and Pharmacogenetics of Thiazolidinediones: Role in Diabetes and Cardiovascular Risk Factors

“…Confirming these findings, by using a quantitative real-time polymerase chain reaction (rt-PCR) Wang et al . [33] evaluated gene expression profiling to assess cardiorenal safety in the heart and kidney tissue samples in adult male myocardial infarction-induced heart failure and Zucker diabetic fatty rats treated with rosiglitazone. Although variations in the expression of some genes such as ACE, PPAR -γ, IL-6 and TNF -α. were observed, authors themselves address serious doubts about the transferability of these results obtained in animal models to clinical settings [34].…”