scholarly journals Cardioprotective effects of polydatin against myocardial injury in diabetic rats via inhibition of NADPH oxidase and NF-κB activities

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ying-Ying Tan ◽  
Lei-Xin Chen ◽  
Ling Fang ◽  
Qi Zhang
Keyword(s):  
Nadph Oxidase ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Myocardial Injury ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Therapeutic Effects ◽  
H9c2 Cells ◽  
Cardioprotective Effects

Abstract Background Diabetic cardiomyopathy is a main cause of the increased morbidity in diabetic patients, no effective treatment is available so far. Polydatin, a resveratrol glucoside isolated from the Polygonum cuspidatum, was found by our and others have antioxidant and cardioprotective activities. Therapeutic effects of polydatin on diabetic cardiomyopathy and the possible mechanisms remains unclear. This study aimed to investigate the cardioprotective effects and underlying mechanisms of polydatin on myocardial injury induced by hyperglycemia. Methods Diabetes in rats was made by high-fat diet combined with multiple low doses of streptozotocin, and then treated with polydatin (100 mg·kg-1·day-1, by gavage) for 8 weeks. Cardiac function was examined by echocardiography. Myocardial tissue and blood samples were collected for histology, protein and metabolic characteristics analysis. In cultured H9c2 cells with 30 mM of glucose, the direct effects of polydatin on myocyte injury were also observed. Results In diabetic rats, polydatin administration significantly improved myocardial dysfunction and attenuated histological abnormalities, as evidenced by elevating left ventricular shortening fraction and ejection fraction, as well as reducing cardiac hypertrophy and interstitial fibrosis. In cultured H9c2 cells, pretreatment of polydatin dose-dependently inhibited high glucose-induced cardiomyocyte injury. Further observation evidenced that polydatin suppressed the increase in the reactive oxygen species levels, NADPH oxidase activity and inflammatory cytokines production induced by hyperglycemia in vivo and in vitro. Polydatin also prevented the increase expression of NOX4, NOX2 and NF-κB in the high glucose -stimulated H9c2 cells and diabetic hearts. Conclusions Our results demonstrate that the cardioprotective effect of polydatin against hyperglycemia-induced myocardial injury is mediated by inhibition of NADPH oxidase and NF-κB activity. The findings may provide a novel understanding the mechanisms of the polydatin to be a potential treatment of diabetic cardiomyopathy.

scholarly journals Melatonin alleviates hyperglycemic-induced cardiomyocyte apoptosis via regulation of long non-coding RNA H19/miR-29c/MAPK axis in diabetic cardiomyopathy

2021 ◽  
Author(s):  
Haitao Tang ◽  
Hongli Zhong ◽  
Wanqing Liu ◽  
Tianfeng Hua ◽  
Yi Wang ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Diabetic Rats ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Assay ◽  
Protective Mechanism ◽  
Diabetic Patients ◽  
Signal Pathways

Abstract BackgroundRecent studies revealed that non-coding RNAs (ncRNAs) play a crucial role in pathophysiological processes involving diabetic cardiomyopathy that contributes to heart failure. The present study was designed to further investigate the anti-apoptotic effect of melatonin on cardiomyocyte in diabetic condition and to elucidate the potential mechanisms associated with ncRNAs. MethodsIn vivo, langendorff-perfusion system and histology staining were used to assess the effect of melatonin on cardiac function. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of ncRNAs. Protein expression levels were assessed by western bolt analysis. In vitro, hoechst 33258 staining and western bolt analysis were used to evaluate the effect of melatonin on apoptosis. We preformed luciferase assay and RNA immunoprecipitation to determine the targets of ncRNAs. RT-qPCR was used to observe the expression of ncRNAs in cardiomyocyte with high glucose treatment.ResultsIn animal models, our results indicated that melatonin notably alleviated cardiac dysfunction and mitigated cardiomyocyte apoptosis in diabetic rats. Interestingly, lncRNA H19 level was increased along with concomitant decrease of miR-29c level in diabetic rats. However, we demonstrated that melatonin significantly downregulated H19 level and upregulated miR-29c level in vivo. In vitro experiments, it has been verified that positive modulation of miR-29c and inhibition of lncRNA H19 as well as mitogen-activated protein kinase (MAPK) pathways distinctly attenuated apoptosis in high glucose-treated H9c2 cells. Luciferase activity assay was conducted to evaluate the potential target sites of miR-29c on lncRNA H19 and MAPK13. LncRNA H19 silencing significantly downregulated the expression of the miR-29c target gene MAPK13 via inducing miR-29c expression. Furthermore, MAPK signal pathways were also affected through regulation of H19 and miR-29c. Most importantly, our results showed that melatonin alleviated hyperglycemic-induced cardiomyocyte apoptosis via inhibiting lncRNA H19/MAPK and increasing miR-29c level in vitro.ConclusionsThese results elucidate a novel protective mechanism of melatonin on diabetic cardiomyocyte apoptosis, which associated with the effect of melatonin on lncRNA H19/miR-29c expression and its downstream MAPK signal pathways, providing a promising strategy for preventing DCM in diabetic patients.

scholarly journals Relaxin Ameliorates Fibrosis in Experimental Diabetic Cardiomyopathy

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3286-3293 ◽  
Author(s):  
Chrishan S. Samuel ◽  
Tim D. Hewitson ◽  
Yuan Zhang ◽  
Darren J. Kelly
Keyword(s):  
Blood Pressure ◽  
Extracellular Matrix ◽  
Diabetic Cardiomyopathy ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Group ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Therapeutic Effects ◽  
Tissue Inhibitor ◽  
Myocardial Stiffness

Fibrosis (extracellular matrix accumulation) is the final end point in diabetic cardiomyopathy. The current study evaluated the therapeutic effects of the antifibrotic hormone relaxin (RLX) in streptozotocin-treated transgenic mRen-2 rats, which undergo pathological and functional features similar to human diabetes. Twelve-week-old hyperglycemic mRen-2 rats, normoglycemic control rats, and animals treated with recombinant human gene-2 (H2) RLX from wk 10–12 were assessed for various measures of left ventricular (LV) fibrosis, hemodynamics, and function, while the mechanism of RLX’s actions was also determined. Hyperglycemic mRen-2 rats had increased LV collagen concentration (fibrosis) and gelatinase activity (all P < 0.05 vs. controls) but equivalent levels of interstitial collagenase and tissue inhibitor of metalloproteinase-1 to that measured in control rats. The increased LV fibrosis associated with diabetic animals led to significant alterations in the E/A wave ratio and E-wave deceleration time (both P < 0.05 vs. controls) in the absence of blood pressure changes, reflective of myocardial stiffness and LV diastolic dysfunction. H2-RLX treatment of diabetic rats led to significant decreases in interstitial and total LV collagen deposition (both P < 0.05 vs. diabetic group), resulting in decreased myocardial stiffness and improved LV diastolic function, without affecting nondiabetic animals. The protective effects of H2-RLX in diabetic rats were associated with a reduction in mesenchymal cell differentiation and tissue inhibitor of metalloproteinase-1 expression in addition to a promotion of extracellular matrix-degrading matrix metalloproteinase-13 (all P < 0.05 vs. diabetic group) but were independent of blood pressure regulation. These findings demonstrate that RLX is an antifibrotic with rapid-occurring efficacy and may represent a novel therapy for the treatment of diabetes.

scholarly journals A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-jie Xing ◽  
Biao-hu Liu ◽  
Shu-jun Wan ◽  
Yi Cheng ◽  
Si-min Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Sglt2 Inhibitor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
H9c2 Cells ◽  
Myocardial Oxidative Stress

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress.

Preparation of Nanocomposite Peptide and Its Inhibitory Effect on Myocardial Injury in Type-II Diabetic Rats

2021 ◽  
Vol 21 (2) ◽  
pp. 1378-1384
Author(s):  
Yang Zhang ◽  
Shaowei Zhuang ◽  
Shengyang Jiang ◽  
Jiehan Zhang ◽  
Yu Chen
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Cardiomyopathy ◽  
Myocardial Injury ◽  
Drug Carrier ◽  
Systolic Dysfunction ◽  
Experimental Studies ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Peptide Drugs

Complications of diabetes are the main cause of death and disability in diabetic patients. Cardiovascular diseases, especially diabetic cardiomyopathy, are one of the major complications and causes of death in type 2 diabetes. Peptide drugs have a better effect on improving cellular oxidative damage, reducing tissue inflammation and inhibiting intracellular calcium overload. The application of nanotechnology to the preparation of peptide drugs and myocardial injury can effectively improve myocardial stun, arrhythmia and myocardial systolic dysfunction in patients with type 2 diabetes. The use of nanotechnology to develop more stable Glucagon-like peptide 1 analogues or sustained-release preparations, improve patient compliance and improve the efficacy of diabetes, is of great significance for the prevention and treatment of diabetic cardiomyopathy. Therefore, this study used nanotechnology to prepare PLGA-GLP-1 nanoparticles using polyglycolic acid glycolic acid as a drug carrier, which achieved long-acting drug and its morphology by transmission electron microscopy. At the same time, this study explored the anti-cardiomyocyte injury and anti-myocardial damage of PLGA-GLP-1 nanocomposite peptide and its molecular mechanism by using animal models and cell models. Experimental studies have shown that PLGA-GLP-1 nanocomposite peptide has a protective effect on myocardial injury in diabetic rats. Its mechanism is related to the PLGA-GLP-1 nanocomposite peptide enhancing the body’s antioxidant capacity, anti-cardiomyocyte apoptosis, and promoting mitochondrial DNA repair in cardiomyocytes.

Abstract 13376: Oral Treatment With a Zinc Complex of Acetylsalicylic Acid Prevents Diabetic Cardiomyopathy in a Rat Model of Type 2 Diabetes

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Sevil Korkmaz-Icöz ◽  
Samer Alsaid ◽  
Tamás Radovits ◽  
Shiliang Li ◽  
Mihály Ruppert ◽  
...  
Keyword(s):  
Oral Administration ◽  
Acetylsalicylic Acid ◽  
Diabetic Cardiomyopathy ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Increased Risk ◽  
Type 2 Diabetic

Introduction: Type 2 diabetic patients are at an increased risk of cardiomyopathy and heart failure is a major cause of death amongst these patients. Growing evidence indicates that proinflammatory cytokines can cause sustained development of insulin resistance and anti-inflammatory medications may reverse this process. Hypothesis: We investigated the effects of an oral administration of zinc and acetylsalicylic acid in the form of bis(aspirinato)zinc(II) complex Zn(ASA)2 on different aspects of cardiac damage in the Zucker diabetic rat (ZDF), an experimental model of type 2 diabetic cardiomyopathy. Methods: The nondiabetic control and the diabetic ZDF rats were pretreated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 30-32 weeks, both the electrical activity and the left ventricular (LV) structural/functional parameters were assessed via electrocardiogram and pressure volume (PV) conductance catheter system. Results: The Zn(ASA)2 treatment significantly decreased the blood glucose concentration (39.6±3.1 vs 50.4±2.6 mM), normalized the impaired LV contractility index (Emax 3.7±0.4 vs 1.9±0.6 mmHg/μl), the passive LV stiffness (end diastolic PV relationship: 0.064±0.008 vs 0.084±0.014 mmHg/μl), and the diastolic dysfunction (LV end diastolic pressure: 6.5±0.6 vs 7.9±0.7 mmHg). Furthermore, the ECG revealed a restoration of the prolonged corrected QT intervals (63±3 vs 83±4 ms, p<0.05) by Zn(ASA)2. A histological examination revealed an increase in the cardiomyocytes transverse cross section area in diabetic rats compared to the controls, which was significantly decreased after Zn(ASA)2. Furthermore, a significant increase in fibrotic formation was observed in the diabetic rats compared to controls, and Zn(ASA)2 administration showed similar collagen content in the ZDF+Zn(ASA)2 rats and in the nondiabetics. A significant increase in the density of TUNEL positive cell nuclei in the diabetic hearts, indicating DNA fragmentation, was significantly decreased by Zn(ASA)2. Additionally, in the diabetic heart, Zn(ASA)2 significantly decreased nitrotyrosine formation. Conclusions: The oral administration of Zn(ASA)2 may have therapeutic potential with the aim of preventing cardiac complications in type 2 diabetic patients.

scholarly journals Exercise Training Attenuates Upregulation of p47phoxand p67phoxin Hearts of Diabetic Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Neeru M. Sharma ◽  
Brandon Rabeler ◽  
Hong Zheng ◽  
Eugenia Raichlin ◽  
Kaushik P. Patel
Keyword(s):  
Exercise Training ◽  
Nadph Oxidase ◽  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Underlying Mechanism ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Cardiac Tissues ◽  
Beneficial Effects ◽  
Collagen Iii

Exercise training (ExT) is currently being used as a nonpharmacological strategy to improve cardiac function in diabetic patients. However, the molecular mechanism(s) underlying its beneficial effects remains poorly understood. Oxidative stress is known to play a key role in the pathogenesis of diabetic cardiomyopathy and one of the enzyme systems that produce reactive oxygen species is NADH/NADPH oxidase. The goal of this study was to investigate the effect of streptozotocin- (STZ-) induced diabetes on expression ofp47phoxandp67phox, key regulatory subunits of NADPH oxidase, in cardiac tissues and determine whether ExT can attenuate these changes. Four weeks after STZ treatment, expression ofp47phoxandp67phoxincreased 2.3-fold and 1.6-fold, respectively, in left ventricles of diabetic rats and these increases were attenuated with three weeks of ExT, initiated 1 week after onset of diabetes. In atrial tissues, there was increased expression ofp47phox(74%), which was decreased by ExT in diabetic rats. Furthermore, increased collagen III levels in diabetic hearts (52%) were significantly reduced by ExT. Taken together, ExT attenuates the increased expression ofp47phoxandp67phoxin the hearts of diabetic rats which could be an underlying mechanism for improving intracardiac matrix and thus cardiac function and prevent cardiac remodeling in diabetic cardiomyopathy.

Long noncoding RNA OIP5-AS1 overexpression promotes viability and inhibits high glucose-induced oxidative stress of cardiomyocytes by targeting microRNA-34a/SIRT1 axis in diabetic cardiomyopathy

2020 ◽  
Vol 21 ◽  
Author(s):  
Haiyun Sun ◽  
Chong Wang ◽  
Ying Zhou ◽  
Xingbo Cheng
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Luciferase Reporter ◽  
H9c2 Cells ◽  
Promoting Effect

Objective: Diabetic cardiomyopathy (DCM) is an important complication of diabetes. This study was attempted to discover the effects of long noncoding RNA OIP5-AS1 (OIP5-AS1) on the viability and oxidative stress of cardiomyocyte in DCM. Methods: The expression of OIP5-AS1 and microRNA-34a (miR-34a) in DCM was detected by qRT-PCR. In vitro, DCM was simulated by high glucose (HG, 30 mM) treatment in H9c2 cells. The viability of HG (30 mM)-treated H9c2 cells was examined by MTT assay. The reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA) levels were used to evaluate the oxidative stress of HG (30 mM)-treated H9c2 cells. Dual-luciferase reporter assay was used to confirm the interactions among OIP5-AS1, miR-34a and SIRT1. Western blot was applied to analyze the protein expression of SIRT1. Results: The expression of OIP5-AS1 was down-regulated in DCM, but miR-34a was up-regulated. The functional experiment stated that OIP5-AS1 overexpression increased the viability and SOD level, while decreased the ROS and MDA levels in HG (30 mM)-treated H9c2 cells. The mechanical experiment confirmed that OIP5-AS1 and SIRT1 were both targeted by miR-34a with the complementary binding sites at 3′UTR. MiR-34a overexpression inhibited the protein expression of SIRT1. In the feedback experiments, miR-34a overexpression or SIRT1 inhibition weakened the promoting effect on viability, and mitigated the reduction effect on oxidative stress caused by OIP5-AS1 overexpression in HG (30 mM)-treated H9c2 cells. Conclusions: OIP5-AS1 overexpression enhanced viability and attenuated oxidative stress of cardiomyocyte via regulating miR-34a/SIRT1 axis in DCM, providing a new therapeutic target for DCM.

scholarly journals The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats

Open Medicine ◽  
2020 ◽  
Vol 16 (1) ◽  
pp. 047-057
Author(s):  
Lei Gong ◽  
Xuyang Wang ◽  
Jinyu Pan ◽  
Mingjun Zhang ◽  
Dian Liu ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Signaling Pathway ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Mtor Signaling ◽  
Maximal Rate ◽  
H9c2 Cells ◽  
Mtor Signaling Pathway ◽  
Cardioprotective Effects

AbstractObjectiveThe purpose of the present study was to evaluate the role of co-treatment of rosuvastatin (RSV) and dapagliflozin (DGZ) preconditioning in myocardium ischemia/reperfusion (I/R) injury and to further investigate the underlying mechanism.MethodsSprague-Dawley (SD) rats (n = 25) were divided into five groups randomly: (1) Sham, (2) I/R, (3) I/R + RSV (10 mg/kg), (4) IR + DGZ (1 mg/kg), and (5) I/R + RSV (10 mg/kg) + DGZ (1 mg/kg). The I/R model was induced with 30 min of left anterior descending occlusion followed by 120 min of reperfusion.ResultsIn vivo pretreatment with RSV and DGZ, respectively, showed a significant reduction of infarction size, a significant increase in the levels of left ventricular systolic pressure, and maximal rate increase in left ventricular pressure (+dp/dtmax), decrease in the levels of left ventricular end-diastolic pressure (LVEDP), maximal rate of decrease of left ventricular pressure (−dp/dtmax) and activity of cardiac enzymes of creatine kinase (CK), creatine kinase MB isoenzymes (CK-MB), and hyper-tensive cardiac troponin I compared with the I/R group. H9C2 cells were exposed to hypoxia/reoxygenation to simulate an I/R model. In vitro administration of 25 µM RSV and 50 µM DGZ significantly enhanced cell viability, upregulated the expression levels of p-PI3K, p-Akt, p-mTOR, and Bcl-2, whereas it downregulated cleaved-caspase3, Bax. TUNEL assay indicated that pretreatment with RSV and DGZ decreased the apoptosis of H9C2 cells.ConclusionThe combination of RSV and DGZ significantly enhances the cardioprotective effects compared with RSV or DGZ alone. RSV and DGZ have the potential cardioprotective effects against I/R injury by activating the PI3K/AKt/mTOR signaling pathway.

Improvement in cardiac dysfunction in streptozotocin-induced diabetic rats following chronic oral administration of bis(maltolato)oxovanadium(IV)

1993 ◽  
Vol 71 (3-4) ◽  
pp. 270-276 ◽  
Author(s):  
Violet G. Yuen ◽  
Chris Orvig ◽  
Katherine H. Thompson ◽  
John H. McNeill
Keyword(s):  
Blood Glucose ◽  
Heart Function ◽  
Myocardial Dysfunction ◽  
Plasma Lipid ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Vanadium Complex ◽  
Significant Correction ◽  
Streptozotocin Diabetic Rats

Decreased cardiac function in streptozotocin-diabetic rats has been used as a model of diabetes-induced cardiomyopathy, which is a secondary complication in diabetic patients. The present study was designed to evaluate the therapeutic effect of a new organic vanadium complex, bis(maltolato)oxovanadium(IV), (BMOV), in improving heart function in streptozotocin-diabetic rats. There were four groups of male, Wistar rats: control (C), control treated (CT), diabetic (D), and diabetic treated (DT). Treatment consisted of BMOV, 0.5 mg/mL (1.8 mM) for the first 3 weeks and 0.75 mg/mL (2.4 mM) for the next 22 weeks, in the drinking water of rats allowed ad libitum access to food and water. BMOV lowered blood glucose to < 9 mM in 70% of DT animals without any increase in plasma insulin levels, and mean blood glucose and plasma lipid levels were significantly lower in DT vs. D rats. Tissue vanadium levels were measured in plasma, bone, kidney, liver, muscle, and fat of BMOV-treated rats. Plasma vanadium levels averaged 0.84 ± 0.07 μg/mL (16.8 μM) in CT rats and 0.76 ± 0.05 μg/mL (15.2 μM) in DT animals. The highest vanadium levels at termination of this chronic feeding study were in bone, 18.3 ± 3.0 μg/g (0.37 μmol/g) in CT and 26.4 ± 2.6 μg/g (0.53 μmol/g) in DT rats, with intermediate levels in kidney and liver, and low, but detectable levels in muscle and fat. There were no deaths in either the CT or DT group, and no overt signs of vanadium toxicity were present. Tissue vanadium levels were not correlated with the glucose-lowering effect. Isolated working heart parameters of left ventricular developed pressure (LVDP) and rate of pressure development (+dP/dT, and −dP/dT) indicated that BMOV treatment resulted in significant correction of the heart dysfunction associated with streptozotocin-induced diabetes in rat.Key words: bis(maltolato)oxovanadium(IV), vanadium, diabetes, streptozotocin, myocardial dysfunction.

scholarly journals PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Miao Chen ◽  
Dian Jing ◽  
Rui Ye ◽  
Jianru Yi ◽  
Zhihe Zhao
Keyword(s):  
Bone Regeneration ◽  
Osteogenic Differentiation ◽  
Bone Healing ◽  
High Glucose ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Regulatory Effect ◽  
Compound C ◽  
High Glucose Condition ◽  
Glucose Condition

Abstract Background Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. Methods We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. Results Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. Conclusion In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

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