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Abstract Background Glucose fluctuations may be involved in the pathophysiological process of cardiomyocyte apoptosis, but the exact mechanism remains elusive. This study focused on exploring the mechanisms related to glucose fluctuation-induced cardiomyocyte apoptosis. Methods Diabetic rats established via an injection of streptozotocin were randomized to five groups: the controlled diabetic (CD) group, the uncontrolled diabetic (UD) group, the glucose fluctuated diabetic (GFD) group, the GFD group rats with the injection of 0.9% sodium chloride (NaCl) (GFD + NaCl) and the GFD group rats with the injection of N-acetyl-L-cysteine (NAC) (GFD + NAC). Twelve weeks later, cardiac function and apoptosis related protein expressions were tested. Proteomic analysis was performed to further analyze the differential protein expression pattern of CD and GFD. Results The left ventricular ejection fraction levels and fractional shortening levels were decreased in the GFD group, compared with those in the CD and UD groups. Positive cells tested by DAB-TUNEL were increased in the GFD group, compared with those in the CD group. The expression of Bcl-2 was decreased, but the expressions of Bax, cleaved caspase-3 and cleaved caspase-9 were increased in response to glucose fluctuations. Compared with CD, there were 527 upregulated and 152 downregulated proteins in GFD group. Txnip was one of the differentially expressed proteins related to oxidative stress response. The Txnip expression was increased in the GFD group, while the Akt phosphorylation level was decreased. The interaction between Txnip and Akt was enhanced when blood glucose fluctuated. Moreover, the application of NAC partially reversed glucose fluctuations-induced cardiomyocyte apoptosis. Conclusions Glucose fluctuations lead to cardiomyocyte apoptosis by up-regulating Txnip expression and enhancing Txnip-Akt interaction.

Background Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Background: Ventricular arrhythmias (VAs) mainly occur in the early post-myocardial infarction (MI) period. However, studies examining the association between total myocardial ischemia time interval and the risk of new-onset VAs during a long-term follow-up are scarce. Methods: This study (symptom-to-balloon time and VEntricular aRrhYthmias in patients with STEMI, VERY-STEMI study) was a multicenter, observational cohort and real-world study, which included patients with ST-segment elevation MI (STEMI) undergoing percutaneous coronary intervention (PCI). The primary endpoint was cumulative new-onset VAs during follow-up. The secondary endpoints were the major adverse cardiovascular events (MACE) and changes in left ventricular ejection fraction (ΔLVEF, %). Results: A total of 517 patients with STEMI were included and 236 primary endpoint events occurred. After multivariable adjustments, compared to patients with S2BT of 24 h-7d, those with S2BT ≤ 24 h and S2BT > 7d had a lower risk of primary endpoint. RCS showed an inverted U-shaped relationship between S2BT and the primary endpoint, with an S2BT of 68.4 h at the inflection point. Patients with S2BT ≤ 24 h were associated with a lower risk of MACE and a 4.44 increase in LVEF, while there was no significant difference in MACE and LVEF change between the S2BT > 7d group and S2BT of 24 h-7d group. Conclusions: S2BT of 24 h-7d in STEMI patients was associated with a higher risk of VAs during follow-up. There was an inverted U-shaped relationship between S2BT and VAs, with the highest risk at an S2BT of 68.4 h.

Abstract Background Glucose fluctuations (GF) are a risk factor for cardiovascular complications associated with type 2 diabetes. However, there is a lack of adequate research on the effect of GF on myocardial fibrosis and the underlying mechanisms in type 2 diabetes. This study aimed to investigate the impact of glucose fluctuations on myocardial fibrosis and explore the potential mechanisms in type 2 diabetes. Methods Sprague Dawley (SD) rats were randomly divided into three groups: the control (Con) group, the type 2 diabetic (DM) group and the glucose fluctuations (GF) group. The type 2 diabetic rat model was established using a high-fat diet combined with low-dose streptozotocin injection and the GF model was induced by using staggered glucose and insulin injections daily. After eight weeks, echocardiography was used to assess the cardiac function of the three groups. Hematoxylin-eosin and Masson staining were utilized to evaluate the degree of pathological damage and fibrosis. Meanwhile, a neonatal rat cardiac fibroblast model with GF was established. Western and immunofluorescence were used to find the specific mechanism of myocardial fibrosis caused by GF. Results Compared with rats in the Con and the DM group, cardiac function in the GF group showed significant impairments. Additionally, the results showed that GF aggravated myocardial fibrosis in vitro and in vivo. Moreover, Ca2+/calmodulin‑dependent protein kinase II (CaMKII) was activated by phosphorylation, prompting an increase in phosphorylation of signal transducer and activator of transcription 3 (Stat3) and induced nuclear translocation. Pretreatment with KN-93 (a CaMKII inhibitor) blocked GF-induced Stat3 activation and significantly suppressed myocardial fibrosis. Conclusions Glucose fluctuations exacerbate myocardial fibrosis by triggering the CaMKII/Stat3 pathway in type 2 diabetes.

Abstract Background Diabetes is associated with myocardial fibrosis, while the underlying mechanisms remain elusive. The aim of this study is to investigate the underlying role of calcineurin/nuclear factor of activated T cell 3 (CaN/NFATc3) pathway and the Enhancer of zeste homolog 2 (EZH2) in diabetes-related myocardial fibrosis. Methods Streptozotocin (STZ)-injected diabetic rats were randomized to two groups: the controlled glucose (Con) group and the diabetes mellitus (DM) group. Eight weeks later, transthoracic echocardiography was used for cardiac function evaluation, and myocardial fibrosis was visualized by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with high-glucose medium with or without cyclosporine A or GSK126. The expression of proteins involved in the pathway was examined by western blotting. The nuclear translocation of target proteins was assessed by immunofluorescence. Results The results indicated that high glucose treatment increased the expression of CaN, NFATc3, EZH2 and trimethylates lysine 27 on histone 3 (H3K27me3) in vitro and in vivo. The inhibition of the CaN/NFATc3 pathway alleviated myocardial fibrosis. Notably, inhibition of CaN can inhibit the nuclear translocation of NFATc3, and the expression of EZH2 and H3K27me3 protein induced by high glucose. Moreover, treatment with GSK126 also ameliorated myocardial fibrosis. Conclusion Diabetes can possibly promote myocardial fibrosis by activating of CaN/NFATc3/EZH2 pathway.

Objective:. Many studies have shown that blood glucose fluctuations (GFs) are more harmful to patients with diabetes mellitus (DM) than sustained hyperglycemia. However, the effect of GF on electrocardiogram (ECG) parameters and vulnerability to ventricular tachycardia/fibrillation (VT/VF) remains poorly characterized. This study aimed to assess the effect of GF on ECG parameters and induction of VT/VF in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats. Methods:. Male Sprague-Dawley rats were injected with STZ and randomly divided into 3 treatment groups: controlled STZ-induced diabetic rats (C-STZ) (n = 10); uncontrolled STZ-induced diabetic rats (U-STZ) (n = 10); and STZ-induced diabetic rats with glucose fluctuations (GF-STZ) (n = 10). After 12 weeks, baseline ECG recordings were taken and a VT/VF test was performed with the administration of caffeine and dobutamine. Hematoxylin & eosin and masson staining were used to evaluate pathological cardiac changes after intervention. Results:. No significant difference in heart rate, RR interval, P wave (duration and height), PR segment, PR interval, QRS wave duration, and T wave height was observed among the 3 groups (P > 0.05). Compared with the C-STZ group, the U-STZ and GF-STZ groups both had a longer T wave duration ((62.41 ± 2.38) ms vs. (78.37 ± 4.64) ms and (96.06 ± 4.60) ms, P < 0.05), QT interval ((83.66 ± 2.31) ms vs. (101.75 ± 4.56) ms and (119.14 ± 4.88) ms, P < 0.05), and QTc interval ((77.45 ± 1.36) ms vs. (91.36 ± 3.49) ms and (104.55 ± 3.01) ms, P < 0.05), all of which were longest in the GF-STZ group (P < 0.05). Additionally, the GF-STZ group had the highest VT/VF occurrence and duration and the highest arrhythmia score. Conclusion:. This study revealed GF can significantly prolong the QT interval, QTc interval, and T wave duration, as well as increase vulnerability to VT/VF in rats, which may be an important electrophysiological mechanism of GF-related ventricular arrhythmia.

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, with its diagnosis being closely tied to higher rates of cardiovascular morbidity and mortality. AF is associated with a range of dangerous complications including stroke and heart failure, making it a key driver of healthcare spending and a major threat to global public health. The precise mechanisms that govern AF incidence and the onset of related complications, however, remain uncertain. Ferroptotic cell death has been the focus of rising interest in the cardiac arrhythmias, and there is recent evidence supporting a role for atrial ferroptosis as a mediator of AF development. Interventional strategies focused on ferroptotic activity, such as novel ferroptosis inhibitors, have also shown promise as a means of protecting against AF through their ability to reduce iron overload. In this review, we provide a summary of the proposed mechanisms whereby ferroptosis contributes to the pathophysiology of AF and their therapeutic implications.

Abstract Dilated cardiomyopathy (DCM) is characterized by the left ventricular dilatation and impaired myocardial systolic dysfunction with high mortality and morbidity. However, the underlying mechanisms remain elusive. We first identified the differentially expressed genes (DEGs) between the DCM and control group using two expression profiles from GSE3585 and GSE84796. Enrichment analysis was conducted to explore the potential mechanisms underlying DCM. A total of four algorithms, including key module of MCODE, degree, maximum neighborhood component (MNC), and maximal clique centrality (MCC), were used to identify the hub genes within Cytoscape. The correlation between hub genes and infiltrated immune cells was evaluated to determine potential immune-related genes. The expression analysis and diagnosis value analysis of potential immune-related genes were performed. Finally, the expression analysis with GSE57338 and relationship analysis with the comparative toxicogenomics database (CTD) were performed to identify the key immune-related genes in DCM. A total of 80 DEGs were screened for DCM. Enrichment analysis revealed that DEGs were involved in the immune-related pathological process. Immune infiltration analysis indicated a potentially abnormal immune response in DCM. Four up-regulated genes (COL1A2, COL3A1, CD53, and POSTN) were identified as potential immune-related genes. Finally, three genes (COL1A2, COL3A1, and POSTN) were determined as the key immune-related genes in DCM via expression analysis with a validation set (GSE57338) and relationship analysis with CTD. Our study suggested that the upregulated COL1A2, COL3A1, and POSTN might be the key immune-related genes for DCM. Further studies are needed to validate the underlying mechanisms.

BackgroundAccumulated clinical studies utilized intracardiac echocardiography (ICE) to guide percutaneous left atrial appendage occlusion (LAAO). However, its procedural success and safety compared to traditional transesophageal echocardiography (TEE) remained elusive. Therefore, we performed a meta-analysis to compare efficacy and safety of ICE and TEE for LAAO.MethodsWe screened studies from four online databases (including the Cochrane Library, Embase, PubMed, and Web of Science) from their inception to 1 December 2022. We used a random or fixed-effect model to synthesize the clinical outcomes and conducted a subgroup analysis to identify the potential confounding factors.ResultsA total of twenty eligible studies with 3,610 atrial fibrillation (AF) patients (1,564 patients for ICE and 2,046 patients for TEE) were enrolled. Compared with TEE group, there was no significant difference in procedural success rate [risk ratio (RR) = 1.01; P = 0.171], total procedural time [weighted mean difference (WMD) = −5.58; P = 0.292], contrast volume (WMD = −2.61; P = 0.595), fluoroscopic time (WMD = −0.34; P = 0.705; I2 = 82.80%), procedural complications (RR = 0.82; P = 0.261), and long-term adverse events (RR = 0.86; P = 0.329) in the ICE group. Subgroup analysis revealed that ICE group might be associated with the reduction of contrast use and fluoroscopic time in the hypertension proportion 50 subgroup and contrast use in multi-center subgroup, respectively.ConclusionOur study suggests that ICE may have comparable efficacy and safety compared to TEE for LAAO.

Abstract Objective We aimed to screen out biomarkers for atrial fibrillation (AF) based on machine learning methods and evaluate the degree of immune infiltration in AF patients in detail. Methods Two datasets (GSE41177 and GSE79768) related to AF were downloaded from Gene expression omnibus (GEO) database and merged for further analysis. Differentially expressed genes (DEGs) were screened out using “limma” package in R software. Candidate biomarkers for AF were identified using machine learning methods of the LASSO regression algorithm and SVM-RFE algorithm. Receiver operating characteristic (ROC) curve was employed to assess the diagnostic effectiveness of biomarkers, which was further validated in another independent validation dataset of GSE14975. Moreover, we used CIBERSORT to study the proportion of infiltrating immune cells in each sample, and the Spearman method was used to explore the correlation between biomarkers and immune cells. Results 129 DEGs were identified, and CYBB, CXCR2, and S100A4 were identified as key biomarkers of AF using LASSO regression and SVM-RFE algorithm. Both in the training dataset and the validation dataset, CYBB, CXCR2, and S100A4 showed favorable diagnostic effectiveness. Immune infiltration analysis indicated that, compared with sinus rhythm (SR), the atrial samples of patients with AF contained a higher T cells gamma delta, neutrophils and mast cells resting, whereas T cells follicular helper were relatively lower. Correlation analysis demonstrated that CYBB, CXCR2, and S100A4 were significantly correlated with the infiltrating immune cells. Conclusions In conclusion, this study suggested that CYBB, CXCR2, and S100A4 are key biomarkers of AF correlated with infiltrating immune cells, and infiltrating immune cells play pivotal roles in AF.

Background: As the most prevalent valvular heart disease, calcific aortic valve disease (CAVD) has become a primary cause of aortic valve stenosis and insufficiency. We aim to illustrate the roles of immune related genes (IRGs) and immune cells infiltration in the occurrence of CAVD.Methods: Integrative meta-analysis of expression data (INMEX) was adopted to incorporate multiple gene expression datasets of CAVD from Gene Expression Omnibus (GEO) database. By matching the differentially expressed genes (DEGs) to IRGs from “ImmPort” database, differentially expressed immune related genes (DEIRGs) were screened out. We performed enrichment analysis and found that DEIRGs in CAVD were closely related to inflammatory response and immune cells infiltration. We also constructed protein–protein interaction (PPI) network of DEIRGs and identified 5 key DEIRGs in CAVD according to the mixed character calculation results. Moreover, CIBERSORT algorithm was used to explore the profile of infiltrating immune cells in CAVD. Based on Spearman’s rank correlation method, correlation analysis between key DEIRGs and infiltrating immune cells was performed.Results: A total of 220 DEIRGs were identified and the enrichment analysis of DEIRGs showed that they were significantly enriched in inflammatory responses. PPI network was constructed and PTPN11, GRB2, SYK, PTPN6 and SHC1 were identified as key DEIRGs. Compared with normal aortic valve tissue samples, the proportion of neutrophils, T cells CD4 memory activated and macrophages M0 was elevated in calcified aortic valves tissue samples, as well as reduced infiltration of macrophages M2 and NK cells activated. Furthermore, key DEIRGs identified in the present study, including PTPN11, GRB2, PTPN6, SYK, and SHC1, were all significantly correlated with infiltration of various immune cells.Conclusion: This meta-analysis suggested that PTPN11, GRB2, PTPN6, SYK, and SHC1 might be key DEIRGs associated with immune cells infiltration, which play a pivotal role in pathogenesis of CAVD.

Hydrogen sulfide (H2S) has been highlighted as an important gasotransmitter in mammals. A growing number of studies have indicated that H2S plays a key role in the pathophysiology of vascular diseases and physiological vascular homeostasis. Alteration in H2S biogenesis has been reported in a variety of vascular diseases and H2S supplementation exerts effects of vasodilation. Accumulating evidence has shown vascular potassium channels activation is involved in H2S-induced vasodilation. This review aimed to summarize and discuss the role of H2S in the regulation of vascular tone, especially by interaction with different vascular potassium channels and the underlying mechanisms.

BackgroundGlucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis.MethodsStreptozotocin (STZ)-injected type 1 diabetic rats were randomized to five groups: the controlled blood glucose (CBG) group, uncontrolled blood glucose (UBG) group, fluctuated blood glucose (FBG) group, FBG rats injected with 0.9% sodium chloride (NaCl) (FBG + NaCl) group, and FBG rats injected with MCC950 (FBG + MCC950) group. Eight weeks later, left ventricular function was evaluated by echocardiography and myocardial fibrosis was observed by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with different concentrations of glucose in vitro.ResultsThe left ventricular function was impaired and myocardial fibrosis was aggravated most significantly in the FBG group compared with the CBG and UBG groups. The levels of interleukin (IL)-1β, IL-18, transforming growth factor-β1 (TGF-β1), collagen type 1 (collagen I), nuclear factor (NF)-κB, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were significantly increased in the FBG group. In vitro, the inhibition of NF-κB and inflammasome reversed these effects. In vivo, NLRP3 inhibition with MCC950 reversed left ventricular systolic dysfunction and myocardial fibrosis induced by glucose fluctuations.ConclusionGlucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.

BackgroundThe long-term outcomes of ablation with vein of Marshall ethanol infusion (VOM-ABL) compared with ablation alone in patients with atrial fibrillation (AF) remains elusive. We aimed to explore whether VOM-ABL showed better long-term benefits and screen the potential determinants of outcome impact of VOM-ABL procedure.MethodsPubMed, Cochrane Library, Web of Science, and Embase were searched up to 1st September 2021. Studies comparing the long-term (one-year or longer) outcomes between VOM-ABL and ablation alone were included. Subgroup analysis identified potential determinants for VOM-ABL procedure.ResultsCompared with ablation alone, VOM-ABL was associated with a significantly higher rate of long-term freedom from AF/AT (risk ratio [RR], 1.28; 95% confidence interval [CI], 1.12–1.47; p = 0.00) and successful mitral isthmus (MI) block (RR, 1.52; 95% CI, 1.16–1.99; p = 0.00), whereas, there was no significant difference in pericardial effusion, stroke/transient ischemic attack (TIA), and all-cause death. Subgroup analysis identified two significant treatment-covariate interactions: one was ablation strategy subgroup (pulmonary vein isolation plus linear and/or substrate ablation [PVI+]; RR, 1.41; 95% CI, 1.27–1.56 vs. PVI; RR, 1.05; 95% CI, 0.92–1.19, p = 0.00 for interaction) for freedom from AF/AT, while the other was VOM-ABL group sample size subgroup (≥ 100; RR, 1.98; 95% CI, 1.24–3.17 vs.

Atrial fibrillation (AF) is one of the most common arrhythmias in medical practice. Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation. The increased morbility of atrial fibrillation in diabetes mellitus is related to both structural and electrical remodeling of atrium. Based on studies of atrial electrophysiological changes in diabetes mellitus, this article focuses on the electrical remodeling of atrial cardiomyocytes, including remodeling of sodium channels, calcium channels, potassium channels and other channels, to provide the basis for the clinical management of antiarrhythmic drugs in diabetic patients with atrial fibrillation.

Diabetic coronary arterial disease is a leading cause of morbidity and mortality in diabetic patients. The impaired function of large-conductance calcium-activated potassium channels (BK channels) is involved in diabetic coronary arterial disease. Many studies have indicated that the reduced BK channel expression in diabetic coronary artery is attributed to ubiquitin-mediated protein degradation by the ubiquitin–proteasome system. This review focuses on the influence and the mechanisms of BK channel regulation by E3 ubiquitin ligases in diabetic coronary arterial disease. Thus, BK channels regulated by E3 ubiquitin ligase may play a pivotal role in the coronary pathogenesis of diabetic mellitus and, as such, is a potentially attractive target for therapeutic intervention.

Accumulating evidence indicates the occurrence and development of diabetic complications relates to not only constant high plasma glucose, but also glucose fluctuations which affect various kinds of molecular mechanisms in various target cells and tissues. In this review, we detail reactive oxygen species and their potentially damaging effects upon glucose fluctuations and resultant downstream regulation of protein signaling pathways, including protein kinase C, protein kinase B, nuclear factor-κB, and the mitogen-activated protein kinase signaling pathway. A deeper understanding of glucose-fluctuation-related molecular mechanisms in the development of diabetic complications may enable more potential target therapies in future.

Sn(II) binds to kaempferol (HKaem, 3,4′,5,7-tetrahydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) at the 3,4-site forming [Sn(II)(Kaem)2] complex in ethanol. DPPH• scavenging efficiency of HKaem is dramatically decreased by SnCl2 coordination due to formation of acid inhibiting deprotonation of HKaem as ligands and thus reduces the radical scavenging activity of the complex via a sequential proton-loss electron transfer (SPLET) mechanism. Moderate decreases in the radical scavenging of HKaem are observed by Sn(CH3COO)2 coordination and by contact between Sn and HKaem, in agreement with the increase in the oxidation potential of the complex compared to HKaem, leading to a decrease in antioxidant efficiency for fruits and vegetables with Sn as package materials.

Aim: Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques.Methods and Results: We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of

Large-conductance calcium-activated potassium channels (BK channels) belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

Background: Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods: In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results: In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion: Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Background: Advanced glycation end products (AGEs) impair vascular physiology in Diabetes mellitus (DM). However, the underlying mechanisms remain unclear. Vascular large conductance calcium-activated potassium (BK) channels play important roles in coronary arterial function. Purpose: Our study aimed to investigate the regulatory role of AGEs in BK channels. Research Design: Using gavage of vehicle (V, normal saline) or aminoguanidine (A) for 8 weeks, normal and diabetic rats were divided into four groups: C+V group, DM+V group, C+A group, and DM+A group. Study Sample: Coronary arteries from different groups of rats and human coronary smooth muscle cells were used in this study. Data Collection and Analysis: Data were presented as mean ± SEM (standard error of mean). Student's t-test was used to compare data between two groups. One-way ANOVA with post-hoc LSD analysis was used to compare data between multiple groups. Results: Compared to the C+V group, vascular contraction induced by iberiotoxin (IBTX), a BK channel inhibitor, was impaired, and BK channel densities decreased in the DM+V group. However, aminoguanidine administration reduced the impairment. Protein expression of BK-β1, phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), and protein kinase B (PKB or Akt) were down-regulated, while F-box protein 32 (FBXO32) expression increased in the DM+V group and in high glucose (HG) cultured human coronary smooth muscle cells. Treatment with aminoguanidine in vitro and in vivo could reverse the above protein expression. The effect of aminoguanidine on the improvement of BK channel function by inhibiting the generation of AGEs was reversed by adding MK2206 (Akt inhibitor) or Compound C (AMPK inhibitor) in HG conditions in vitro. Conclusions: AGEs aggravate BK channel dysfunction via the AMPK/Akt/FBXO32 signaling pathway. [ABSTRACT FROM AUTHOR]