GW0742 activates peroxisome proliferator‐activated receptor δ to reduce free radicals and alleviate cardiac hypertrophy induced by hyperglycemia in cultured H9c2 cells

Cheng, Kai‐Chun; Chang, Wei‐Ting; Li, Yingxiao; Cheng, Yung-Ze; Chen, Zhih‐Cherng

doi:10.1002/jcb.27270

Cited by 9 publications

(8 citation statements)

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“…Following our previous report 46 , we estimated the mRNA level of each signaling target gene in current study. Briefly, TRIzol reagent (Invitrogen, Carlsbad, CA, USA) is applied to extract the total RNA from cell lysates.…”

Section: Methodsmentioning

confidence: 99%

TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

Cheng

Chang

Kuo

et al. 2019

Sci Rep

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Left ventricular hypertrophy is an independent risk factor in diabetic patients. TGR5 is shown to express in hearts, but its functional role in diabetes-induced cardiac hypertrophy remained unclear. The current study investigated the role of TGR5 on high glucose-induced hypertrophy of H9C2 cells. After incubation with a high level of glucose, H9C2 cells showed hypertrophic responses. Activation of TGR5 by lithocholic acid (LCA) ameliorated cell hypertrophy and enhanced SERCA2a and phosphorylated phospholamban (PLN) expression in H9C2 cells. Triamterene inhibited these effects at an effective dose to block TGR5. However, LCA failed to modify the free radical elevation induced by high-glucose in the H9c2 cells. Moreover, PKA inhibitors, but not an Epac blocker, markedly improved hyperglycemia-induced hypertrophy and attenuated the increased SERCA2a expression by LCA; it also attenuated the phosphorylated PLN and SERCA2a protein expression levels in high glucose-treated H9C2 cells. In conclusion, TGR5 activation stimulated protein kinase A (PKA) to enhance PLN phosphorylation, which activated SERCA2a to remove Ca 2+ from cytosol to sarcoplasmic reticulum in addition to the reduction of calcineurin/NFAT pathway signaling to ameliorate the hyperglycemia-induced cardiac hypertrophy shown in cardiomyocytes. TGR5 may service as a new target in the control of diabetic cardiomyopathy.

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Section: Methodsmentioning

confidence: 99%

TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

Cheng

Chang

Kuo

et al. 2019

Sci Rep

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“…Hyperglycaemia is important in the pathogenesis of diabetic disorders, and lung injury by hyperglycaemia has been demonstrated in diabetic rats [7]. However, damage to the heart by hyperglycaemia is less common, except for cardiac hypertrophy [8].…”

Section: Introductionmentioning

confidence: 99%

Cardiac TGR5 expression enhanced by hyperglycaemia in diabetic rats: A preclinical warning for disorders with excess bile acids

Kuo¹,

Lee²,

Cheng³

et al. 2019

Integr Mol Med

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Background: Diabetes is a risk factor for cardiovascular disorders. TGR5 levels are increased in cardiomyocytes exposed to hyperglycaemia. The objective of this study was to investigate the potential mechanism(s) for the increase in TGR5 levels in the hearts of diabetic rats. Materials and methods:We used streptozotocin -induced diabetic rats (STZ rats) to assess the role of hyperglycaemia in increased cardiac TGR5 levels. The expression levels of TGR5 and signal transducer and activator of transcription 3, both its phosphorylated form (p-STAT3) and its native form (STAT3), in heart tissues were measured using Western blots. Results:The increased levels of TGR5 and the ratio of p-STAT3 to STAT3 in cardiac tissues exposed to hyperglycaemic conditions were reversed by treating the hyperglycaemia. Additionally, the potential mechanisms of this effect were confirmed in a cultured rat cardiac cell line (H9c2) incubated in high-glucose (HG) medium to mimic the changes observed in vivo. TGR5 expression increased in parallel with the increased ratio of p-STAT3 and STAT3 in H9c2 cells exposed to HG, and these effects were reversed by treatment with stattic at a dose sufficient to inhibit STAT3. Similarly, the antioxidant tiron also produced the same effects in H9c2 cells. Conclusion:Increased cardiac TGR5 levels in a type-1 diabetes model were related to hyperglycaemia, which produces free radicals to activate STAT3 for the higher expression of TGR5 in the heart. Therefore, an elevation in circulating bile acids from hepatic disorders and/or others shall be handled carefully in diabetic patients.

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“…This antioxidant activity of PPARδ is directly linked to the inhibitory effect on hypertrophy of vascular smooth muscle cells stimulated by Ang II [ 28 ]. In fact, multiple studies have demonstrated that pharmacological activation of PPARδ by specific ligands can improve cardiac hypertrophy in cellular and animal models through mechanisms not yet fully elucidated [ 13 , 29 , 30 , 31 ]. By contrast, other reports have demonstrated that inducible conditional expression of PPARδ in cardiac endothelial cells leads to rapid cardiac angiogenesis and growth, including increased cardiomyocyte size [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we previously demonstrated that ligand-activated PPARδ counteracts ROS production in vascular cells to inhibit cellular senescence induced by Ang II [ 9 ]. It has also been demonstrated that PPARδ activation inhibits cardiac hypertrophy induced by Ang II and hyperglycemia through suppression of the intracellular Ca 2+ signaling pathway and free radical production in cultured H9c2 cardiomyocytes [ 12 , 13 ]. Based on its ability to protect the cardiovasculature [ 8 , 9 , 10 , 11 , 12 ], investigating the potential mechanisms of PPARδ in the development of cardiac hypertrophy could prove fruitful from a therapeutic perspective.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, GW501516-activated PPARδ reduced ROS accumulation, thereby relieving Ang II-induced hypertrophy of myocardial cells. Although PPARδ elicited beneficial effects in opposition to oxidative stress-induced vascular damage by inhibiting ROS generation in diverse cell lineages [ 9 , 10 , 11 , 12 , 13 , 14 , 17 ], little is known about actual effector molecules involved in this mechanism. We identified catalase as an effector molecule in the PPARδ-mediated reduction of ROS accumulation, thereby preventing cardiac hypertrophy induced by Ang II.…”

Section: Introductionmentioning

confidence: 99%

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Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes

et al. 2021

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Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor δ (PPARδ) is involved in the anti-hypertrophic activity of PPARδ in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPARδ by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPARδ, indicating that PPARδ mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPARδ significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPARδ also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPARδ on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPARδ are mediated through catalase induction. Furthermore, GW501516-activated PPARδ exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPARδ may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.

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GW0742 activates peroxisome proliferator‐activated receptor δ to reduce free radicals and alleviate cardiac hypertrophy induced by hyperglycemia in cultured H9c2 cells

Cited by 9 publications

References 50 publications

TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

Cardiac TGR5 expression enhanced by hyperglycaemia in diabetic rats: A preclinical warning for disorders with excess bile acids

Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes

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