Effects of Chronic PPAR-Agonist Treatment on Cardiac Structure and Function, Blood Pressure, and Kidney in Healthy Sprague-Dawley Rats

Abstract

PPAR-γ agonists have been associated with heart failure (HF) in diabetic patients. These incidences have been reported mostly in patient populations who were at high risk for HF or had pre-existing impaired cardiovascular function. However, whether there are similar effects of these agents in subjects with no or reduced cardiovascular pathophysiology is not clear. In this study, the effects of chronic treatment with PD168, a potent peroxisome proliferator activated receptor (PPAR) subtype-γ agonist with weak activity at PPAR-α, and rosiglitazone (RGZ), a less potent PPAR-γ agonist with no PPAR-α activity, were evaluated on the cardiovascular-renal system in healthy male Sprague-Dawley (SD) rats by serial echocardiography and radiotelemetry. Rats were treated with vehicle (VEH), PD168, @ 10 or 50 mg/kg·bw/day (PD-10 or PD-50, resp.) or RGZ @ 180 mg/kg·bw/day for 28 days (n = 10/group). Relative to VEH, RGZ, and both doses of PD168 resulted in a significant fall in blood pressure. Furthermore, RGZ and PD168 increased plasma volume (% increase from baseline) 18%, 22%, and 48% for RGZ, PD-10, and PD-50, respectively. PD168 and RGZ significantly increased urinary aldosterone excretion and heart-to-body weight ratio relative to VEH. In addition, PD168 significantly decreased (10–16%) cardiac ejection fraction (EF) and increased left ventricular area (LVA) in systole (s) and diastole (d) in PD-10 and -50 rats. RGZ significantly increased LVAd; however, it did not affect EF relative to VEH. In conclusion, chronic PPAR-γ therapy may predispose the cardiorenal system to a potential sequela of structural and/or functional changes that may be deleterious with regard to morbidity and mortality.

Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

“…However, PIO tended to enhance rather than reverse diabetic cardiac hypertrophy, as indicated by the reduction of myocyte density. This structural alteration is a typical consequence of PPAR-γ activation and appears to be caused by fluid accumulation and hemodynamic overload [34]. Additional findings about direct myocardial actions of PPAR-γ are ambiguous.…”

Peroxisomes in cardiomyocytes and the peroxisome / peroxisome proliferator-activated receptor-loop

“…PPARs have also been inextricably linked to the regulation of cardiac metabolism because of their ability to interlink and control different metabolic pathways in response to the nutritional status of the cell (63,64). A large variety of lipid derivatives that are metabolised exclusively inside peroxisomes (▶ Figure 1) serve as ligands for the activation of PPARs.…”

Current perspective of pathophysiological and interventional effects on endothelial progenitor cell biology: Focus on Pi3K/AKT/eNOS pathway

“…The response to VEGF was also abrogated in hyperglycemic endothelial cells by PPARγ agonists but could be restored by insulin supplementation. This effect of PPARγ treatment could be responsible for serious inhibition of reendothelialization in insulin-resistant patients, for instance after coronary interventions [145]. The apparent contradiction between the effects of TZDs on EPCs and ECs is possibly due to differences in intracellular transduction pathways and different culture conditions, shifting cells in a pro-or anti-angiogenic state, which could explain the observed differences in cellular behaviour.…”