Pharmacogenomic, physiological, and biochemical investigations on safety and efficacy biomarkers associated with the peroxisome proliferator-activated receptor-gamma activator rosiglitazone in rodents: a translational medicine investigation.
Peroxisome proliferator-activated receptor (PPAR)-gamma 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-gamma 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 = 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-alpha). HF was confirmed by increase in cardiac brain natriuretic peptide expression (p < 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 beta 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.
Wang
Xinkang
X
Discovery Translational Medicine, Pfizer, Collegeville, Pennsylvania, USA. wangxk2000@yahoo.com
Liu
Xiaorong
X
Zhan
Yutian
Y
Lavallie
Edward R
ER
Diblasio-Smith
Liz
L
Collins-Racie
Lisa
L
Mounts
William M
WM
Rutkowski
J Lynn
JL
Xu
Xin
X
Goltsman
Ilia
I
Abassi
Zaid
Z
Winaver
Joseph
J
Feuerstein
Giora Z
GZ
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001835:Body Weight; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D006439:Hemodynamics / Q000502:physiology; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D009205:Myocarditis / Q000139:chemically induced / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D047495:PPAR gamma / Q000819:agonists*; D012313:RNA / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000493:pharmacokinetics; D057170:Translational Research, Biomedical
D015415:Biomarkers; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D012313:RNA