Oxidative stress and inflammation modulate peroxisome proliferator‐activated receptors with regional discrepancy in diabetic heart

Lee, Ting-Wei; Kao, Yu Hsun; Chen, Yao Chang; Pan, Nan; Chen, Yi Jen

doi:10.1111/j.1365-2362.2010.02318.x

Cited by 39 publications

(48 citation statements)

References 40 publications

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“…Expression of PPARα may be induced by LXR through the LXRE present in its promoter region [49]. Myocardial expression of PPARα and PPARδ genes is down-regulated in streptozotocin diabetic rats [50][51][52][53] which is in agreement with our observations. Interestingly, in our study administration of TO901317 reversed these changes.…”

Section: Discussionsupporting

confidence: 92%

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

Harasiuk

Baranowski²,

Zabielski³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Liver X receptors (LXRα and LXRβ) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in the heart, and enhanced LXR activity in the streptozotocin (STZ) diabetic myocardium was reported recently. The aim of this study was to investigate effect of in vivo LXR activation on myocardial lipid metabolism under conditions of STZ-induced diabetes. Methods: Wistar rats were randomly divided into three experimental groups: non-diabetic control, treated with STZ, and treated with STZ and LXR agonist - TO901317. Diabetes was induced by a single intraperitonal injection of STZ at a dose of 55 mg/kg. LXR agonist was administrated once daily in the morning by an oral gavage at a dose of 10 mg/kg/d during the last week of the experiment. After anesthesia samples of blood and the left ventricle were taken. Results: TO901317 administration increased expression of both LXR isoforms and its target genes: sterol response element binding protein 1c (SREBP-1c) and acetyl-coenzyme A carboxylase 1 (ACC1) in the heart of streptozotocin-diabetic rats. Treatment with LXR agonist had no effect on plasma lipids and glucose in the diabetic rats. Concomitantly, content of the examined lipid classes in the diabetic heart (nonesterified fatty acids, triacylglycerols, phospholipids, cholesterol esters, ceramide) was unchanged after treatment with TO901317. On the contrary, myocardial level of cholesterol and diacylglycerols (DAG) was decreased after LXR activation in diabetic rats, the change in DAG level was associated with downregulated expression of adipose triglyceride lipase (ATGL). Conclusion: Activation of LXRs by TO901317 protects cardiomyocytes against DAG accumulation and thus may reverse disturbances in lipid metabolism observed in streptozotocin-diabetic heart.

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Section: Discussionsupporting

confidence: 92%

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

Harasiuk

Baranowski²,

Zabielski³

et al. 2016

Cell Physiol Biochem

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“…x AE s. n=8, **P<0.01 vs. normal; ## P<0.01 vs. STZ; $ P<0.05 vs. AMG Expression of PPARα is sensitive to oxidant and inflammatory reactions and is modulated by non-PPARα agonists such as antioxidant and anti-inflammatory agents, as we found in the present study. Ascorbic acid has been proved to correct abnormal expression of PPARs toward normal, together with downregulated NADPH oxidase found in diabetic heart (Lee et al 2010). Intervention with berberine relieves renal complications of diabetes by elevating expression of PPARα significantly Noh et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue

Xia

Dai

et al. 2011

Naunyn-Schmied Arch Pharmacol

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Diabetic nephropathy (DN) due to microvascular complication is a serious status characterized by continuously progressive until occurrence of the end stage of renal disease. It is attractive to investigate further mechanisms underlying the entity of DN and new drug discovery. We hypothesized that the entity of DN is inflammatory and is characterized by upregulated inflammatory/pro-inflammatory factors such as peroxisome proliferator-activated receptor alpha, NADPH oxidase, endoplasmic reticulum stress (ER stress), and endothelin receptor A (ET(A)) and downregulated connexin 43 (Cx43) in the kidney. Aminoguanidine is a special blocker to advanced glycation end products and argirein, a new compound contains a molecule of rhein linked to L: -arginine by a hydrogen bond. Rhein possesses anti-inflammatory activity and has been chemically modified to produce a new compound diacerein launched in European market for treating osteoarthritis. Argirein with two active molecules rhein and L: -arginine may be effective in suppressing the inflammatory cytokines contributing to the pathogenesis of DN. With a single injection of streptozotocin 65 mg/kg, ip in rats, early diabetic nephropathy was produced and revealed as an increased microalbuminuria, elevated creatinine and urea in serum, associated with upregulation of mRNA and protein of NADPH oxidase p22phox, p47phox, and p67phox and ET(A), upregulated PKR-like eukaryotic initiation factor 2α kinase (PERK), and downregulated Cx43 in the renal tissue. Upregulation of PERK suggested that there is an ER stress involved in the diabetic kidney, along with an increase in inflammatory/pro-inflammatory factors indicating an entity of chronic inflammation. Abnormalities of biomarkers were blunted by either aminoguanidine or argirein significantly. The new compound argirein is potential in alleviating and retarding microvascular complications of diabetes such as DN in clinical settings.

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“…In addition, cardiac-restricted overexpression of PPAR-α and PPAR-γ caused deranged myocardial energy metabolism, which contributed to cardiomyopathy [5,6]. Our previous study has also found that DM (diabetes mellitus) can modulate PPARs in cardiomyocytes through increased inflammatory cytokines and oxidative stress [7]. Therefore PPARs play a critical role in the pathogenesis of diabetic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 96%

Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes

et al. 2011

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Hypertension and DM (diabetes mellitus) are common chronic disorders that often co-exist. DM and PPAR (peroxisome-proliferator-activated receptor)-γ agonists may directly impair heart function. However, the effects of DM and PPAR-γ agonists on hypertensive myocardium are not known. Hence the aim of the present study was to investigate whether DM and a PPAR-γ agonist [RGZ (rosiglitazone)] modulated the effects of hypertension on myocardial expression of PPAR isoforms. Cardiac PPAR isoforms, TNF (tumour necrosis factor)-α and IL (interleukin)-6 were evaluated by real-time PCR and Western blotting in SHRs (spontaneously hypertensive rats), diabetic SHRs, diabetic SHRs treated with RGZ (5 mg/kg of body weight) and control WKY (Wistar-Kyoto) rats. Cardiac NADPH oxidase activity was quantified using a SOD (superoxide dismutase)-sensitive cytochrome c reduction assay. When compared with hearts from control WKY rats, hearts from SHRs had decreased PPAR-α and PPAR-δ mRNA and protein levels (39 and 44% respectively for PPAR-α, and 37 and 42% respectively for PPAR-δ), but had increased PPAR-γ mRNA and protein levels (1.9- and 1.4-fold respectively). The hypertension-induced changes in mRNA and protein of cardiac PPAR isoforms were enhanced in diabetic SHRs, which were attenuated in diabetic SHRs treated with RGZ. Cardiac TNF-α and IL-6 protein levels and NADPH oxidase activities were increased in SHRs and were increased further in diabetic SHRs. RGZ treatment decreased TNF-α and IL-6 protein levels and NADPH oxidase activities in hearts from diabetic SHRs. In conclusion, these findings suggest that DM and the PPAR-γ agonist modulated the hypertensive effects on cardiac PPAR isoform expression.

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Oxidative stress and inflammation modulate peroxisome proliferator‐activated receptors with regional discrepancy in diabetic heart

Abstract: Peroxisome proliferator-activated receptor isoforms are differentially expressed in the atria and ventricles. Diabetes can modulate PPARs through increased inflammatory cytokines and oxidative stress, which are attenuated by ascorbate treatment.

Cited by 39 publications

References 40 publications

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue

Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes

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