Activation of peroxisome proliferator-activated receptor gamma inhibits endothelin-1-induced cardiac hypertrophy via the calcineurin/NFAT signaling pathway

2008 ◽  
Vol 317 (1-2) ◽  
pp. 189-196 ◽  
Author(s):  
Yingxia Bao ◽  
Ruifang Li ◽  
Jianmin Jiang ◽  
Birong Cai ◽  
Jie Gao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelin 1

scholarly journals Endogenously produced adiponectin protects cardiomyocytes from hypertrophy by a PPARγ-dependent autocrine mechanism

2010 ◽  
Vol 299 (3) ◽  
pp. H690-H698 ◽  
Author(s):  
Rajesh H. Amin ◽  
Suresh T. Mathews ◽  
Adebisi Alli ◽  
Todd Leff
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Receptor Gene ◽  
Peroxisome Proliferator ◽  
Adrenergic Stimulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Culture Models

In experimental animal and cell culture models, activation of peroxisome proliferator-activated receptor (PPAR) γ in heart has been shown to have beneficial effects on cardiac function and cardiomyocyte physiology. The goal of this study was to identify the signaling pathway by which PPARγ activation protects cardiomyocytes from the deleterious effects of hypertrophic stimuli. In primary cardiomyocyte cultures, we found that genetic or pharmacological activation of PPARγ protected cells from cardiac hypertrophy induced by α-adrenergic stimulation. Examination of gene expression in these cells revealed a surprising increase in the expression of adiponectin in cardiomyocytes and secretion of the high-molecular-weight form of the hormone into media. Using RNAi to block PPARγ-induced adiponectin production or adiponectin receptor gene expression, we found that the PPARγ-mediated anti-hypertrophic effect required cardiomyocyte-produced adiponectin, as well as an intact adiponectin signaling pathway. Furthermore, mice expressing constitutive-active PPARγ and cardiomyocyte specific adiponectin expression were protected from high-fat diet-induced cardiac hypertrophy and remodeling. These findings demonstrate that functional adiponectin hormone can be produced from the heart and raise the possibility that beneficial effects of PPARγ activation in heart could be due in part to local production of adiponectin that acts on cardiomyocytes in an autocrine manner.

Peroxisome proliferator-activated receptor-γ activators inhibit endothelin-1-related cardiac hypertrophy in rats

2002 ◽  
Vol 103 (s2002) ◽  
pp. 16S-20S ◽  
Author(s):  
Satoshi SAKAI ◽  
Takashi MIYAUCHI ◽  
Yoko IRUKAYAMA-TOMOBE ◽  
Takehiro OGATA ◽  
Katsutoshi GOTO ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Sham Operation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelin 1 ◽  
Vehicle Treatment ◽  
Pioglitazone Treatment

Endothelin-1 (ET-1) causes cardiac hypertrophy, and ET receptor antagonists inhibit the development of cardiac hypertrophy in vitro and in vivo. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the family of nuclear receptors, suppresses activator protein-1 (AP-1). We investigated the effects of the thiazolidinediones troglitazone and pioglitazone, activators of PPARγ, on cardiac hypertrophy due to pressure overload provoked by abdominal aortic banding (AB) in rats. Rats were divided into four groups: sham operation with vehicle treatment (n = 5); AB surgery with vehicle treatment (n = 6); AB surgery with troglitazone treatment (100mg·kg-1·day-1; n = 5); and AB surgery with pioglitazone treatment (10mg·kg-1·day-1; n = 8). Treatments were started 7 days before AB surgery, and left ventricular (LV) hypertrophy was assessed 24h after surgery. The ratio of LV weight/body weight (BW) was significantly increased in AB rats compared with sham-operated rats; treatment of AB rats with troglitazone or pioglitazone significantly inhibited the increase in LV weight/BW. Expression of ET-1 mRNA was markedly enhanced in the left ventricles of AB rats; treatment with troglitazone or pioglitazone lowered expression significantly. Suppression of cardiac hypertrophy by pioglitazone treatment was accompanied by a decrease in expression of the gene encoding brain natriuretic factor, a molecular marker for cardiac hypertrophy, in AB rats. Because the ET-1 gene has AP-1 response elements in its 5´-flanking region, the thiazolidinediones troglitazone and pioglitazone may inhibit cardiac hypertrophy partly through suppression of AP-1-induced ET-1 gene up-regulation.

Gabapentin Reduces Alcohol Intake in Rats by Regulating NF-κB Signaling Pathway Via PPAR γ

2021 ◽  
Author(s):  
Jing Li ◽  
Kewei Xu ◽  
Hao Ding ◽  
Qiaozhen Xi
Keyword(s):  
Locomotor Activity ◽  
Signaling Pathway ◽  
Specific Inhibitor ◽  
Underlying Mechanism ◽  
Ethanol Consumption ◽  
Diglycidyl Ether ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α

Abstract Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

scholarly journals Anxa2 gene silencing attenuates obesity-induced insulin resistance by suppressing the NF-κB signaling pathway

2019 ◽  
Vol 316 (2) ◽  
pp. C223-C234 ◽  
Author(s):  
Yong Wang ◽  
Yun-Sheng Cheng ◽  
Xiao-Qiang Yin ◽  
Gang Yu ◽  
Ben-Li Jia
Keyword(s):  
Insulin Resistance ◽  
Gene Silencing ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Cell Model ◽  
Global Scale ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Insulin resistance (IR) continues to pose a major threat to public health due to its role in the pathogenesis of metabolic syndrome and its ever-increasing prevalence on a global scale. The aim of the current study was to investigate the efficacy of Anxa2 in obesity-induced IR through the mediation of the NF-κB signaling pathway. Microarray analysis was performed to screen differentially expressed genes associated with obesity. To verify whether Anxa2 was differentially expressed in IR triggered by obesity, IR mouse models were established in connection with a high-fat diet (HFD). In the mouse IR model, the role of differentially expressed Anxa2 in glycometabolism and IR was subsequently detected. To investigate the effect of Anxa2 on IR and its correlation with inflammation, a palmitic acid (PA)-induced IR cell model was established, with the relationship between Anxa2 and the NF-κB signaling pathway investigated accordingly. Anxa2 was determined to be highly expressed in IR. Silencing Anxa2 was shown to inhibit IR triggered by obesity. When Anxa2 was knocked down, elevated expression of phosphorylated insulin receptor substrate 1 (IRS1), IRS1 and peroxisome proliferator-activated receptor coactivator-1a, and glucose tolerance and insulin sensitivity along with 2-deoxy-d-glucose uptake was detected, whereas decreased expression of suppressor of cytokine signaling 3, IL-6, IL-1β, TNF-α, and p50 was observed. Taken together, the current study ultimately demonstrated that Anxa2 may be a novel drug strategy for IR disruption, indicating that Anxa2 gene silencing is capable of alleviating PA or HFD-induced IR and inflammation through its negative regulatory role in the process of p50 nuclear translocation of the NF-κB signaling pathway.

Abstract 15931: Glycogen Synthase Kinase-3α Plays a Critical Role in the Development of Cardiac Dysfunction During Obesity and Insulin Resistance Through Phosphorylation of Peroxisome Proliferator-Activated Receptor α

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Insulin Resistance ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Cardiac Dysfunction ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Obesity and insulin resistance (IR) lead to impaired cardiac metabolism, resulting in cardiac dysfunction. However, the underlying mechanisms responsible for the development of cardiac dysfunction remain poorly understood. PPARα serves as a key regulator of fatty acid (FA) metabolism in the heart. GSK-3α, a serine/threonine kinase, was dephosphorylated at S21 and activated (2.0 fold, p<0.05) in the hearts of obese mice fed a high-fat diet (HFD) and ob/ob mice. To evaluate the functional significance of GSK-3α upregulation, wild-type (WT) and cardiac specific GSK-3α heterozygous knockout (cGSK-3α HKO) mice were fed a HFD for up to 14 weeks. There was no difference in the food intake or body weight change between WT and cGSK-3α HKO mice. However, cardiac hypertrophy and diastolic dysfunction observed in WT mice were significantly ameliorated in cGSK-3α HKO mice after HFD feeding (8.1± 0.6 and 6.5±0.5, LVW/TL; 24.8±0.9 and 16.6±0.8, deceleration time (DT), all p<0.05). FA oxidation (FAO) (0.81 fold) and ectopic lipid accumulation (Oil Red O staining) were significantly decreased in cGSK-3α HKO mice than in WT mice after HFD feeding. GSK-3α, but not GSK-3β, directly interacted with and phosphorylated PPARα at the ligand binding domain in cardiomyocytes (CMs) and in the heart. PPARα phosphorylation in the heart was significantly increased (2.1 fold, p<0.05) in response to HFD, but it was attenuated in cGSK-3α HKO mice (0.74 fold, p<0.05). Fenofibrate, a PPARα ligand, inhibited GSK-3α-induced PPARα phosphorylation (0.81 fold, p<0.05), reduced ectopic lipid accumulation, FAO (0.84 fold, p<0.05), and attenuated diastolic dysfunction (25.5±3.1 and 18.6±2.5, DT; 0.16±0.04 and 0.08±0.02, EDPVR, all p<0.05) in the heart of HFD fed mice. Collectively, these results suggest that GSK-3α increases PPARα activity through phosphorylation of PPARα, which is inhibited by Fenofibrate. Activation of GSK-3α and consequent phosphorylation of PPARα during obesity and IR could play an important role in the development of cardiac hypertrophy and diastolic dysfunction. Synthetic PPARα ligands inhibit GSK-3α-mediated phosphorylation of PPARα, thereby paradoxically attenuating excessive FA metabolism in cardiomyocytes.

Regulator 1-Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Signaling Pathway in Investigating the Pathological Characteristics and Molecular Mechanism of Liver Cirrhosis Complicated by Acute Kidney Injury

2022 ◽  
Vol 12 (1) ◽  
pp. 112-120
Author(s):  
Jieqi Gong ◽  
Huanhua Lu
Keyword(s):  
Acute Kidney Injury ◽  
Liver Cirrhosis ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Kidney Injury ◽  
Male Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Duct Ligation

The objective of this study was to investigate the molecular mechanism of the histopathological characteristics of liver cirrhosis (LC) complicated with acute kidney injury (AKI) and the signaling pathway of silent information regulator 1 (SIRT1)-peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) during the pathogenesis of LC. 20 healthy male rats with AKI complicated by laparoscopic cholecystectomy were selected and divided randomly into control group (C group), lipopolysaccharide (LPS) group, bile duct ligation (BDL) group, and model group (lipopolysaccharide+BDL) (D group). The indexes of all the rats were determined, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), sarcoplasmic enzyme (Scr), and blood urea nitrogen (BUN); the SIRT1 and PGC-1α expressions in renal tissues of rats from each group was detected. Results showed that the AST and ALT levels in BDL group and D group were higher markedly than those before surgery (P < 0.05). The serum levels of Scr and BUN in D group 4 hours after LPS injection increased hugely compared with before injection (P < 0.05). Compared with BDL group, the protein levels of SIRT1 and PGC-1α in renal tissue of group D were decreased sharply (P < 0.05), and the SIRT1 protein expression was positively correlated with PGC-1α (r = 0.836 and P < 0.01). When LC were complicated with AKI, SIRT1 activity was reduced and PGC-1α expression was inhibited. Moreover, SIRT1-PGC-1α signaling pathway played a protective role in pathogenesis of LC complicated with AKI.

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