Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator

2002 ◽  
Vol 283 (3) ◽  
pp. H949-H957 ◽  
Author(s):  
Ellen Aasum ◽  
Darrell D. Belke ◽  
David L. Severson ◽  
Rudolph A. Riemersma ◽  
Marie Cooper ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Cardiac Metabolism ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Hearts from diabetic db/ db mice, a model of Type 2 diabetes, exhibit left ventricular failure and altered metabolism of exogenous substrates. Peroxisome proliferator-activated receptor-α (PPAR-α) ligands reduce plasma lipid and glucose concentrations and improve insulin sensitivity in db/ db mice. Consequently, the effect of 4- to 5-wk treatment of db/ db mice with a novel PPAR-α ligand (BM 17.0744; 25–38 mg · kg−1 · day−1), commencing at 8 wk of age, on ex vivo cardiac function and metabolism was determined. Elevated plasma concentrations of glucose, fatty acids, and triacylglycerol (34.0 ± 3.6, 2.0 ± 0.4, and 0.9 ± 0.1 mM, respectively) were reduced to normal after treatment with BM 17.0744 (10.8 ± 0.6, 1.1 ± 0.1, and 0.6 ± 0.1 mM). Plasma insulin was also reduced significantly in treated compared with untreated db/ db mice. Chronic treatment of db/ db mice with the PPAR-α agonist resulted in a 50% reduction in rates of fatty acid oxidation, with a concomitant increase in glycolysis (1.7-fold) and glucose oxidation (2.3- fold). Correction of the diabetes-induced abnormalities in systemic and cardiac metabolism after BM 17.0744 treatment did not, however, improve left ventricular contractile function.

scholarly journals PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis

2017 ◽  
Vol 312 (2) ◽  
pp. H239-H249 ◽  
Author(s):  
Stephen W. Standage ◽  
Brock G. Bennion ◽  
Taft O. Knowles ◽  
Dolena R. Ledee ◽  
Michael A. Portman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Mouse Models ◽  
Heart Function ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Regulatory State ◽  
Peroxisome Proliferator Activated Receptor

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα ( Ppara−/−) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara−/− mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara−/− mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara−/− mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. NEW & NOTEWORTHY In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.

Mechanism of cardiomyocyte PGC-1α gene regulation by ERRα

2013 ◽  
Vol 91 (3) ◽  
pp. 148-154 ◽  
Author(s):  
Angela Ramjiawan ◽  
Rushita A. Bagchi ◽  
Laura Albak ◽  
Michael P. Czubryt
Keyword(s):  
Cardiac Metabolism ◽  
Luciferase Reporter ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Impaired Metabolism ◽  
Repressive Effect ◽  
Evolutionarily Conserved ◽  
Reporter Assays

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) regulates critical genes involved in cardiac mitochondrial biogenesis and fatty acid oxidation, and its loss is associated with impaired metabolism and various cardiac pathologies. Estrogen-related receptor α (ERRα) targets many of the same genes as PGC-1α, and extensive cross talk exists between these 2 regulators. Here we report the identification of an evolutionarily conserved ERRα binding site within the PGC-1α promoter. Using luciferase reporter assays and overexpression, inhibition, or knockdown of ERRα, we show that PGC-1α expression is critically dependent upon ERRα in primary cardiomyocytes. We demonstrate that short-term hypoxia results in reduced ERRα mRNA expression, which precedes a similar loss of PGC-1α mRNA. However, chromatin immunoprecipitation reveals that despite a key role for ERRα in regulating PGC-1α in normoxic cardiomyocytes, ERRα loss is not responsible for PGC-1α loss in hypoxia. Histone deacetylase 5 (HDAC5) has previously been demonstrated to strongly inhibit expression of PGC-1α, and we show that overexpression of ERRα is sufficient to overcome this repressive effect. Our data elucidates the mechanism by which ERRα regulates cardiac PGC-1α gene expression, and suggests that ERRα may provide a means to normalize PGC-1α expression that could be useful in the development of strategies aimed at improving cardiac metabolism in disease.

Co-expression of skeletal and cardiac troponin T decreases mouse cardiac function

2008 ◽  
Vol 294 (1) ◽  
pp. C213-C222 ◽  
Author(s):  
Q.-Q. Huang ◽  
H. Z. Feng ◽  
J. Liu ◽  
J. Du ◽  
L. B. Stull ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Troponin T ◽  
Ex Vivo ◽  
Heart Function ◽  
Left Ventricular Pressure ◽  
Experimental System ◽  
Left Ventricular ◽  
Negative Effects

In contrast to skeletal muscles that simultaneously express multiple troponin T (TnT) isoforms, normal adult human cardiac muscle contains a single isoform of cardiac TnT. To understand the significance of myocardial TnT homogeneity, we examined the effect of TnT heterogeneity on heart function. Transgenic mouse hearts overexpressing a fast skeletal muscle TnT together with the endogenous cardiac TnT was investigated in vivo and ex vivo as an experimental system of concurrent presence of two classes of TnT in the adult cardiac muscle.This model of myocardial TnT heterogeneity produced pathogenic phenotypes: echocardiograph imaging detected age-progressive reductions of cardiac function; in vivo left ventricular pressure analysis showed decreased myocardial contractility; ex vivo analysis of isolated working heart preparations confirmed an intrinsic decrease of cardiac function in the absence of neurohumoral influence. The transgenic mice also showed chronic myocardial hypertrophy and degeneration. The dominantly negative effects of introducing a fast TnT into the cardiac thin filaments to produce two classes of Ca2+ regulatory units in the adult myocardium suggest that TnT heterogeneity decreases contractile function by disrupting the synchronized action during ventricular contraction that is normally activated as an electrophysiological syncytium.

Pioglitazone prevents cardiac remodeling in high-fat, high-calorie-induced Type 2 diabetes mellitus

2006 ◽  
Vol 291 (1) ◽  
pp. H81-H87 ◽  
Author(s):  
Walter E. Rodriguez ◽  
Irving G. Joshua ◽  
Jeff C. Falcone ◽  
Suresh C. Tyagi
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Left Ventricular ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Calorie Diet

The agonists of peroxisome proliferator-activated receptor-γ (PPARγ) ameliorate cardiovascular complications associated with diabetes mellitus. We tested the hypothesis that recovery from ailing to failing myocardium in diabetes by PPARγ agonist is in part due to decreased matrix metalloproteinase-9 (MMP-9) activation and left ventricular (LV) tissue levels of homocysteine (Hcy). C57BL/6J mice were made diabetic (D) by feeding them a high-fat calorie diet. PPARγ was activated by adding pioglitazone (Pi) to the diet. After 6 wk, mice were grouped into: normal calorie diet (N), D, N + Pi and D + Pi ( n = 6 in each group). LV variables were measured by echocardiography, endothelial-myocyte (E-M) coupling was measured in cardiac rings, and MMP-9 activation was measured by zymography. Blood glucose levels were twofold higher in D mice compared with N mice. Pi decreased the levels of glucose in D mice to the levels in N mice. LV Hcy levels were 3.5 ± 0.5 μM in N groups compared with 12.4 ± 0.6 μM in D groups. Treatment with Pi normalized the LV levels of Hcy but had no effect on plasma levels of Hcy. In the D group, LV contraction was reduced compared with that of the N group and was ameliorated by treatment with Pi. LV wall thickness was reduced to 0.25 ± 0.02 mm in the D group compared with 0.42 ± 0.01 mm in the N group. LV diastolic diameter was 3.05 ± 0.01 mm in the D group compared with 2.20 ± 0.02 mm in the N group. LV systolic diameter was 1.19 ± 0.02 mm in the D group and 0.59 ± 0.01 mm in the N group. Pi normalized the LV variables in D mice. The responses to ACh and nitroprusside were attenuated in diabetic hearts, suggesting that there was E-M uncoupling in the D group compared with the N group, which was ameliorated by Pi. Plasma and LV levels of MMP-2 and -9 activities were higher in the D group than in the N group but normalized after Pi treatment. These results suggest that E-M uncoupling in the myocardium, in part, is due to increased MMP activities secondary to suppressing PPARγ activity in high-fat, calorie-induced Type 2 diabetes mellitus.

Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice

2011 ◽  
Vol 300 (6) ◽  
pp. H2116-H2122 ◽  
Author(s):  
Ahmed M. Khalid ◽  
Anne Dragøy Hafstad ◽  
Terje S. Larsen ◽  
David L. Severson ◽  
Neoma Boardman ◽  
...  
Keyword(s):  
Antioxidant Property ◽  
Cardiac Metabolism ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Antidiabetic Therapy ◽  
Tetradecylthioacetic Acid ◽  
Ppar Ligand ◽  
Type 2 Diabetic

Tetradecylthioacetic acid (TTA) is a novel peroxisome proliferator-activated receptor (PPAR) ligand with marked hypolipidemic and insulin-sensitizing effects in obese models. TTA has recently been shown to attenuate dyslipidemia in patients with type 2 diabetes, corroborating the potential for TTA in antidiabetic therapy. In a recent study on normal mice, we showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. The aim of the present study was, therefore, to elucidate the effects of TTA treatment (0.5%, 8 days) on cardiac metabolism and function in a hyperlipidemic type 2 diabetic model. We found that TTA treatment increased myocardial FA oxidation, not only in nondiabetic ( db/+) mice but also in diabetic ( db/db) mice, despite a clear lipid-lowering effect. Although TTA had deleterious effects in hearts from nondiabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts, TTA improved ischemic tolerance, an effect that is most likely related to the antioxidant property of TTA. The present study strongly advocates the need for investigation of the cardiac effects of PPAR ligands used in antidiabetic/hypolipidemic therapy, because of their pleiotropic properties.

Deletion of peroxisome proliferator-activated receptor-α induces an alteration of cardiac functions

2006 ◽  
Vol 291 (1) ◽  
pp. H161-H166 ◽  
Author(s):  
Cécile Loichot ◽  
Laurence Jesel ◽  
Angela Tesse ◽  
Antonia Tabernero ◽  
Kristina Schoonjans ◽  
...  
Keyword(s):  
Heart Rate ◽  
Myocardial Fibrosis ◽  
Ex Vivo ◽  
Left Ventricular ◽  
P Wave ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Intraventricular Conduction ◽  
Cardiac Functions

The peroxisome proliferator-activated receptor-α (PPARα) plays a major role in the control of cardiac energy metabolism. The role of PPARα on cardiac functions was evaluated by using PPARα knockout (PPARα −/−) mice. Hemodynamic parameters by sphygmomanometric measurements show that deletion of PPARα did not affect systolic blood pressure and heart rate. Echocardiographic measurements demonstrated reduced systolic performance as shown by the decrease of left ventricular fractional shortening in PPARα −/− mice. Telemetric electrocardiography revealed neither atrio- nor intraventricular conduction defects in PPARα −/− mice. Also, heart rate, P-wave duration and amplitude, and QT interval were not affected. However, the amplitude of T wave from PPARα −/− mice was lower compared with wild-type (PPARα +/+) mice. When the myocardial function was measured by ex vivo Langendorff's heart preparation, basal and β-adrenergic agonist-induced developed forces were significantly reduced in PPARα-null mice. In addition, Western blot analysis shows that the protein expression of β1-adrenergic receptor is reduced in hearts from PPARα −/− mice. Histological analysis showed that hearts from PPARα −/− but not PPARα +/+ mice displayed myocardial fibrosis. These results suggest that PPARα-null mice have an alteration of cardiac contractile performance under basal and under stimulation of β1-adrenergic receptors. These effects are associated with myocardial fibrosis. The data shed light on the role of PPARα in maintaining cardiac functions.

Abstract 61: miRNA-21 Targets Left Ventricular Peroxisome Proliferator-activated Receptor Alpha in a Rat Model of Type 4 Cardiorenal Syndrome

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alison J Kriegel ◽  
Mingyu Liang ◽  
Yong Liu ◽  
Pengyuan Liu ◽  
Allen W Cowley ◽  
...  
Keyword(s):  
Protein Expression ◽  
Rat Model ◽  
Molecular Mechanisms ◽  
Cardiorenal Syndrome ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cardiac Pathology ◽  
Receptor Alpha

Type 4 cardiorenal syndrome (CRS4) is a condition in which chronic kidney disease (CKD) contributes to cardiovascular pathology including cardiac dysfunction, left ventricular (LV) hypertrophy, atherosclerosis, and heart failure. We have used a rat model of CKD, the 5/6 nephrectomy (5/6 NX), to study molecular mechanisms that mediate the development of cardiac pathology in CRS4. We previously reported that the upregulation of microRNA miR-21-5p (miR-21) in the left ventricle (LV) was accompanied by pathological remodeling and a drop in fractional shortening in adult male Sprague Dawley rats 7 weeks after 5/6 NX. Systemic knockdown of miR-21 in 5/6 NX rats with LNA-modified anti-miR-21 improved cardiac function, however it did not reduce the modest fibrosis observed with our 5/6 NX model or upregulate miR-21 targets identified in other models of cardiac pathology, suggesting a novel cardiac target for miR-21 in this model. Through next-generation mRNA sequencing of LV tissues from anti-miR-21 treated rats, and subsequent Ingenuity Pathway Analysis, we have found cardioprotective alterations in genes related to cardiac hypertrophy, metabolism, immune and inflammatory signaling, and atherosclerosis. Suppression or reduction of miR-21 target peroxisome proliferator-activated receptor alpha (PPARa), a master regulator of fatty acid oxidation, has been reported to be involved in all of these processes. Translational suppression of PPARa through miR-21 has been confirmed in other tissues, but not in the myocardium. The average LV PPARa protein expression level was significantly reduced (-37.7 ± 5.4%) in the 5/6 NX model and restored by miR-21 knockdown (Western blot; n=5-6/group; mean ± SEM). Immunohistochemistry revealed that the pronounced alterations in PPARa expression occurred within cardiomyocytes (CMs) in these samples. Transfection of neonatal CMs with pre-miR-21, significantly reduced PPARa protein expression within 48 hours (-23.0 ± 0.9%; n=3/group). These data indicate that PPARa suppression by miR-21 occurs within LV in 5/6 NX model of CKD and that miR-21 can regulate PPARa in CMs. This regulation may be relevant in other models of chronic cardiac disease where increased miR-21 and suppression of PPARa have been independently reported.

PPAR-γ agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation

2005 ◽  
Vol 288 (1) ◽  
pp. H77-H82 ◽  
Author(s):  
Shintaro Nemoto ◽  
Peter Razeghi ◽  
Masakuni Ishiyama ◽  
Gilberto De Freitas ◽  
Heinrich Taegtmeyer ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Lipid Accumulation ◽  
Contractile Function ◽  
Left Ventricular ◽  
Peroxisome Proliferator ◽  
Adrenergic Blockade ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
K Index ◽  
Triglyceride Accumulation

Previously we reported that the beneficial effects of β-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 ± 0.11*; 3 mo MR, 2.12 ± 0.34; baseline, 4.01 ± 0.29; ANOVA, P = 0.038; * P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-γ agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.

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