Study of Thiazolidinedione-Induced Plasma Volume Expansion and Cardiac Hypertrophy

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a critical transcription factor mediating metabolism in diverse tissues or cells. The PPARγ agonist thiazolidinediones (TZDs), including rosiglitazone (Rosi) and pioglitazone (Pio), are used clinically to treat type 2 diabetes. However, much concern of TZDs has arisen regarding critical side effects on heart. Although TZD-induced cardiac hypertrophy has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, the true causative roles have not yet been established. To test the hypothesis that plasma volume expansion directly mediates Rosi-induced cardiac hypertrophy, mice were fed a high-fat diet with Rosi and cardiac and metabolic consequences were examined. Rosi treatment induced plasma volume expansion and cardiac hypertrophy in wild-type and PPARγ heterozygous knockout (Pparg+/-) mice, but not in a mutant strain of mice defective for ligand binding (PpargP465L/+). Co-treatment with the diuretic furosemide (Furo) in wild-type mice attenuated Rosi-induced plasma volume expansion, cardiac hypertrophy, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Interestingly, glucose and lipid metabolism genes in the heart were altered by Rosi, while these changes were not attenuated by Furo co-treatment. Similar changes were also observed when mice were treated with Pio. Other diuretics, including spironolactone and tricholormethiazide, but not amiloride, attenuated Rosi effects on plasma volume expansion and cardiac hypertrophy. Importantly, Rosi-mediated whole-body metabolic improvements were not affected by Furo co-treatment. Together, we evidenced that releasing plasma volume by diuretics lowers side effects of TZD-induced plasma volume expansion and cardiac events without compromising TZD’s actions in metabolic switch in the heart and whole-body insulin sensitivity. This is a strategy that could be immediately adopted without withdrawal of TZDs and testing new drugs that target PPARγ.

Date of Award	2014
Original language	English
Supervisor	Pei-Jane Tsai (Supervisor)