Treatment of type 2 diabeticdb/dbmice with a novel PPARγ agonist improves cardiac metabolism but not contractile function

Abstract

Treatment of type 2 diabetic db/db mice with a novel PPAR␥ agonist improves cardiac metabolism but not contractile function. Am J Physiol Endocrinol Metab 286: E449-E455, 2004. First published November 4, 2003 10.1152/ajpendo.00329.2003.-Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferatoractivated receptor-␥ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K ϩ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization. diabetic cardiomyopathy; cardiac metabolism PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARs) are ligand-activated transcription factors within the nuclear receptor superfamily (11). PPARs heterodimerize with retinoid X receptors and bind to specific DNA response elements in the promoter region of target genes.Three PPAR isoforms (␣, ␤/␦, ␥) can be distinguished by expression patterns and activation by relatively selective ligands. PPAR␣ and PPAR␤/␦ are widely expressed (13, 28). PPAR␣ is activated by hypolipidemic fibrate drugs (23). PPAR␣ regulates a wide variety of target genes involved in catabolism of lipids (5). PPAR␣ is highly expressed in the heart; Barger and Kelly (5) have suggested that cardiac PPAR␣ plays a role in metabolic remodeling. In general, cardiac PPAR␣ expression correlates with capacity for fatty acid (FA) oxidation (26). Studies with cultured cardiomyocytes incubated with selective PPAR␣ ligands have revealed specific target genes that regulate FA uptake and intracellular binding and cellular FA oxidative metabolism. As a consequence, PPAR␣ activation by selective ligands enhanced rates of FA oxidation (14,24,47). Because FA are endogenous ligands for cardiac PPAR␣, oxidative capacity of the heart can be regulated according to FA delivery. Interestingly, activation of cardiac PPAR␤/␦ also stimulated expression of FA-metabolizing genes (24).PPAR␥ expression is more restrictive (11). In adipose tissue, PPAR␥ promotes differentiation and lipid storage (37). PPAR␥ agonists augment insulin sensitivity (35, 48); consequently, thiazolidinediones that activate PPAR...

Cardiac Functional Analysis by Electrocardiography, Echocardiography and in situ Hemodynamics in Streptozotocin-Induced Diabetic Mice

“…A few studies used echocardiography to evaluate cardiac dysfunction in diabetic mouse models including both type 1 15,30) and type 2 diabetes. 14,31,32) In regarding to type 1 diabetes, our results are consistent with study of Shiomi et al 30) and inconsistent with the study of Nielsen et al 15) which revealed a slight increase in LVEDD and LVESD in diabetic mice 3 months after STZ treatment. These discrepancies may be due to the use of anesthesia, 10,33) the duration of diabetes 34) and, perhaps more importantly, the type of diabetic models.…”

“…These discrepancies may be due to the use of anesthesia, 10,33) the duration of diabetes 34) and, perhaps more importantly, the type of diabetic models. For instance, in the studies of Shiome et al 30) and the present study, tribromoethanol/amylene hydrate (Avertin) was used, and in the study of Nielsen et al 15) hypnorm/diazepam (1 : 1) was used, while in other studies, 14,32) no anesthesia was used. In addition, we examined a single-high-dose STZ-induced type 1 diabetic model, which is same as that in the study by Shiome et al, 30) whereas others used either type 2 diabetes (db/db mice or high-fat-induced diabetes) 14,31,32) or type-1 diabetes induced by multiplelow dose of STZ.…”

“…For instance, in the studies of Shiome et al 30) and the present study, tribromoethanol/amylene hydrate (Avertin) was used, and in the study of Nielsen et al 15) hypnorm/diazepam (1 : 1) was used, while in other studies, 14,32) no anesthesia was used. In addition, we examined a single-high-dose STZ-induced type 1 diabetic model, which is same as that in the study by Shiome et al, 30) whereas others used either type 2 diabetes (db/db mice or high-fat-induced diabetes) 14,31,32) or type-1 diabetes induced by multiplelow dose of STZ. 15) Compared to single-high dose of STZ, diabetes induced by multiple-low doses of STZ has significantly different mechanisms for the development of diabetes.…”

Rodent models of diabetic cardiomyopathy

“…Using echocardiography, reduced fractional shortening and a reduction in the velocity of circumferential shortening have been demonstrated (Semeniuk et al, 2002;Carley et al, 2004;Pereira et al, 2006). Cardiac output, LV-developed pressure and cardiac power are all reduced in isolated, working db/db hearts, whereas LV end diastolic pressure is increased (Belke et al, 2000;Aasum et al, 2003;Carley et al, 2004;Hafstad et al, 2006;Hafstad et al, 2007). Similar contractile deficits are observed in Langendorff-perfused db/db hearts, in which ±dP/dt, peak systolic pressure, rate pressure product and developed pressure are all reduced Disease Models & Mechanisms DMM PERSPECTIVE .…”

Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart

“…Because expression of Angptl4 is increased by PPAR␥ activation both in vitro and in vivo, a role of Angptl4 in mediating the biological activity of thiazolidinediones (TZDs) has been suggested (13). Notably, treatment with TZDs has been shown to be associated with increased incidence of cardiac hypertrophy and diminished cardiac fatty acid catabolism in preclinical species (16)(17)(18). However, the molecular events leading to this observation remain elusive.…”