Cardiomyocyte specific peroxisome proliferator-activated receptor-α overexpression leads to irreversible damage in ischemic murine heart

Duerr, Georg Daniel; Heinemann, Jan C.; Arnoldi, Vanessa; Feißt, Andreas; Kley, Julian; Ghanem, Alexander; Welz, Armin; Dewald, Oliver

doi:10.1016/j.lfs.2014.03.019

Cited by 31 publications

(32 citation statements)

References 48 publications

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“…Pharmacological activation of PPARα 8–12 weeks post-myocardial ischemia aggravates cardiac hypertrophy 61 . Similarly, isolated hearts from either α MHC-Ppara mice or mice that are subjected to ischemia/reperfusion and are treated with a PPARα agonist have lower cardiac power 62 and increased infarct size 63 . On the other hand, PPARα activation improves contractile function and reduces infarct size in isolated perfused rat hearts following ischemia/reperfusion 64 .…”

Section: Discussionmentioning

confidence: 99%

Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Drosatos

Pollak

Pol

et al. 2016

Circulation Research

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Rationale Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown. Objective To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara. Methods and Results We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels. Conclusions Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.

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Section: Discussionmentioning

confidence: 99%

Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Drosatos

Pollak

Pol

et al. 2016

Circulation Research

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“…6 ). Peroxisome proliferator-activated receptor (PPAR)-alpha is downregulated in ischemic myocardium and has been found to play a role in the switch from fatty acid oxidation to glucose consumption [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Glucose and fatty acid metabolism in infarcted heart from streptozotocin-induced diabetic rats after 2 weeks of tissue remodeling

Malfitano

Souza

Carbonaro

et al. 2015

Cardiovasc Diabetol

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BackgroundThe effects of streptozotocin (STZ)-induced diabetes on heart metabolism and function after myocardial infarction (MI) remodelling were investigated in rats.MethodsFifteen days after STZ (50 mg/kg b.w. i.v.) injection, MI was induced by surgical occlusion of the left coronary artery. Two weeks after MI induction, contents of glycogen, ATP, free fatty acids and triacylglycerols (TG) and enzyme activities of glycolysis and Krebs cycle (hexokinase, glucose-6-phosphate dehydrogenase, phosphofructokinase, citrate synthase) and expression of carnitine palmitoyl-CoA transferase I (a key enzyme of mitochondrial fatty acid oxidation) were measured in the left ventricle (LV). Plasma glucose, free fatty acids and triacylglycerol levels were determined. Ejection fraction (EF) and shortening fraction (SF) were also measured by echocardiography.ResultsGlycogen and TG contents were increased (p < 0.05) whereas ATP content was decreased in the LV of the non-infarcted diabetic group when compared to the control group (p < 0.05). When compared to infarcted control rats (MI), the diabetic infarcted rats (DI) showed (p < 0.05): increased plasma glucose and TG levels, elevated free fatty acid levels and increased activity of, citrate synthase and decreased ATP levels in the LV. Infarct size was smaller in the DI group when compared to MI rats (p < 0.05), and this was associated with higher EF and SF (p < 0.05).ConclusionsSystolic function was preserved or recovered more efficiently in the heart from diabetic rats two weeks after MI, possibly due to the high provision of glucose and free fatty acids from both plasma and heart glycogen and triacylglycerol stores.

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“…Therefore, the current study results could emphasize the association of diabetes and myocardial metabolism in connection with insulin resistance, and suggest that beneficial effects of an adequate glycemic control on myocardial metabolic disturbances in diabetes. These metabolic disturbances may lead to diabetic cardiomyopathy, however, further studies of the relationship between myocardial glucose uptake and cardiac function will be needed to determine the exact mechanisms [ 46 – 48 ].…”

Section: Discussionmentioning

confidence: 99%

Visceral adiposity is associated with altered myocardial glucose uptake measured by 18FDG-PET in 346 subjects with normal glucose tolerance, prediabetes, and type 2 diabetes

Kim

et al. 2015

Cardiovasc Diabetol

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BackgroundThe heart requires constant sources of energy mostly from free fatty acids (FFA) and glucose. The alteration in myocardial substrate metabolism occurs in the heart of diabetic patients, but its specific association with other metabolic variables remains unclear. We aimed to evaluate glucose uptake in hearts of subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes mellitus (T2DM) using [18F]-fluorodeoxyglucose-positron emission tomography (18FDG-PET) in association with visceral and subcutaneous adiposity, and metabolic laboratory parameters.MethodsA total of 346 individuals (NGT, n = 76; prediabetes, n = 208; T2DM, n = 62) in a health promotion center of a tertiary hospital were enrolled. The fasting myocardial glucose uptake, and visceral and subcutaneous fat areas were evaluated using 18FDG-PET and abdominal computed tomography, respectively.ResultsMyocardial glucose uptake was significantly decreased in subjects with T2DM compared to the NGT or prediabetes groups (p for trend = 0.001). Multivariate linear regression analyses revealed that visceral fat area (β = −0.22, p = 0.018), fasting FFA (β = −0.39, p < 0.001), and uric acid levels (β = −0.21, p = 0.007) were independent determinants of myocardial glucose uptake. Multiple logistic analyses demonstrated that decreased myocardial glucose uptake (OR 2.32; 95 % CI 1.02–5.29, p = 0.045) and visceral fat area (OR 1.02, 95 % CI 1.01–1.03, p = 0.018) were associated with T2DM.ConclusionsOur findings indicate visceral adiposity is strongly associated with the alteration of myocardial glucose uptake evaluated by 18FDG-PET, and its association further relates to T2DM.

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Cardiomyocyte specific peroxisome proliferator-activated receptor-α overexpression leads to irreversible damage in ischemic murine heart

Cited by 31 publications

References 48 publications

Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Glucose and fatty acid metabolism in infarcted heart from streptozotocin-induced diabetic rats after 2 weeks of tissue remodeling

Visceral adiposity is associated with altered myocardial glucose uptake measured by 18FDG-PET in 346 subjects with normal glucose tolerance, prediabetes, and type 2 diabetes

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