Pathogenesis Of Diabetic Cardiomyopathy Research Articles

Tom70 protects against diabetic cardiomyopathy through its antioxidant and antiapoptotic properties.

Mitochondrial dysfunction plays a critical role in the pathogenesis of diabetic cardiomyopathy. Translocase of mitochondrial outer membrane 70 (Tom70) primarily facilitates the import of mitochondrial preproteins that may be involved in the regulation of oxidative stress and mitochondrial function. This study aimed to investigate the role of Tom70 in the development of myocardial injury in leptin receptor-deficient (db/db) diabetic mice. Tom70 siRNA or an overexpressing lentivirus was intramuscularly injected into mouse hearts or used to treat cultured neonatal cardiomyocytes. We found that Tom70 was downregulated in the diabetic hearts compared with the level in the wild-type hearts and that knocking down Tom70 exacerbated cardiac hypertrophy, fibrosis, and ventricular dysfunction in the db/db mice. Similarly, the in vitro data demonstrated that silencing Tom70 enhanced high-glucose and high-fat (HGHF) medium treatment-induced mitochondrial superoxide production, decreased ATP production and the mitochondrial membrane potential, and enhanced cell apoptosis in neonatal cardiomyocytes. Importantly, overexpression of Tom70 alleviated HGHF medium-induced oxidative stress, mitochondrial dysfunction, and cell apoptosis. Furthermore, in vivo data confirmed that reconstitution of Tom70 ameliorated cardiac hypertrophy, interstitial fibrosis, and ventricular dysfunction in the db/db mice. In addition, Tom70 overexpression mitigated mitochondrial fragmentation and dysfunction in the hearts of the db/db mice. Taken together, these findings suggest that downregulation of Tom70 contributes to the development of diabetic cardiomyopathy and that reconstitution of Tom70 may be a new therapeutic strategy for the prevention and treatment of diabetic cardiomyopathy.

Activation of calcium‑sensing receptor‑mediated autophagy in high glucose‑induced cardiac fibrosis invitro.

Myocardial fibrosis is a major complication of diabetic cardiomyopathy (DCM) that is primarily caused by cardiac fibroblasts that are highly activated by persistent hyperglycemic stimulation, resulting in excessive collagen deposition. Calcium sensing receptor (CaSR) is a member of the G protein-coupled receptor superfamily and regulates intracellular calcium concentrations, which are associated with numerous diseases, including myocardial infarction, tumors and pulmonary hypertension. However, whether CaSR participates in the pathological process of myocardial fibrosis in DCM remains unknown. The present study aimed to investigate the mechanism via which CaSR regulates high glucose (HG)-induced cardiac fibrosis in vitro. HG treated-cardiac fibroblast (CFs) were used and western blotting, immunoprecipitation, Cell Counting Kit-8 assay, ELISA and transfection technology were performed to examine the role of CaSR. In the HG group, treatment with HG increased CaSR, α-smooth muscle actin, collagen I/III and matrix metalloproteinase 2/9 expression and enhanced autophagosome generation and CF proliferation. Furthermore, CaSR activation upregulated the expression of Smad ubiquitin regulatory factor 2 (Smurf2), which led to increased intracellular Ca2+ concentrations, increased ubiquitination levels of SKI like proto-oncogene and Smad7 and autophagy activation. Furthermore, the CaSR agonist (R568) or the CaSR inhibitor (Calhex231) and Smurf2-small interfering RNA promoted or inhibited HG-induced alterations, including the enhanced and weakened effects, respectively. Taken together, the results from the present study suggested that increased CaSR expression in CFs activated the Smurf2-ubiquitin proteasome and autophagy, causing excessive CF proliferation and extensive collagen deposition, which resulted in HG-induced myocardial fibrosis. These findings indicated a novel pathogenesis of DCM and may provide a novel strategy for the diagnosis and treatment of DCM.

Expression profiling of circular RNAs and their potential role in early‑stage diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a severe cardiovascular complication of diabetes mellitus (DM). Detecting DCM during the early stages of the disease remains a challenge, as the molecular mechanisms underlying early-stage DCM are not clearly understood. Circular RNA (circRNA), a type of non-coding RNA, has been confirmed to be associated with numerous diseases. However, it is still unclear how circRNAs are involved in early-stage DCM. In the present study, heart tissues harvested from BKS-db/db knock-out mice were identified through high-throughput RNA sequencing technology. A total of 58 significantly differentially expressed circRNAs were identified in the db/db sample. Among these, six upregulated circRNAs and seven downregulated circRNAs were detected by reverse transcription-quantitative PCR and analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Furthermore, based on the predicted binding site with microRNAs (miRNAs) involved in DCM, five circRNAs (mmu_circ_0000652, mmu_circ_0000547, mmu_circ_0001058, mmu_circ_0000680 and novel_circ_0004285) were shown to serve as competing endogenous (ce)RNAs. The corresponding miRNAs and mRNAs of the ceRNAs were also verified, and two promising circRNA-miRNA-mRNA regulatory networks were determined. Finally, internal ribosome entry site prediction combined with open reading frame prediction indicated that it was highly possible that mmu_circ_0001160 encoded a protein. In the present study, a comprehensive analysis of the circRNA expression profile during the early phase of DCM was performed, and two promising circRNA-miRNA-mRNA regulatory networks were identified. These results lay the foundation for unravelling the underlying pathogenesis of DCM, and highlight potential biomarkers and therapeutic targets for the treatment of DCM at an early stage.

Inhibition of miR-223 attenuates the NLRP3 inflammasome activation, fibrosis, and apoptosis in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is an independent and specific cardiomyopathy, which is associated with cardiac failure in diabetic patients. Currently, the pathogenesis of DCM is a popular research topic in the investigation of cardiovascular diseases. MicroRNAs (miRNAs) have been identified as the latent therapeutic targets for DCM. However, the functions and complex mechanisms of miRNAs in DCM have not been clarified. The cardiomyocyte injury model was established using high glucose (HG) ingestion, and the DCM rat model was established using 30 mg/kg streptozotocin. MicroRNA-223 (miR-223) expression was determined using qRT-PCR; the levels of NLRP3 inflammasome, fibrosis, and apoptosis-related genes and proteins were analyzed using qRT-PCR and western blot assays. Besides the morphological changes and fibrosis of myocardial tissues were evaluated using H&E and Masson staining. We discovered that miR-223 was highly expressed in the HG-induced cardiomyocyte injury model, and miR-223 inhibitor could further relieve the myocardial fibrosis and apoptosis, and inhibit NLRP3 inflammasome of HG-induced H9c2 cells. Additionally, we found that inhibition of miR-223 had obvious positive effects on the cardiac dysfunction and reduced the elevation of blood sugar in the DCM model rats. We found that the miRNA-223 inhibitor could improve the morphological structure and the degree of fibrosis in myocardial tissues in the DCM model rats. Moreover, we verified that inhibition of miR-223 could suppress the NLRP3 inflammasome activation, and alleviate myocardial fibrosis and apoptosis of the DCM model rats. In conclusion, our results suggested that miR-223 might be an underlying therapeutic target for DCM by reducing NLRP3 inflammasome activation, fibrosis, and apoptosis.

NLRC5 deficiency ameliorates cardiac fibrosis in diabetic cardiomyopathy by regulating EndMT through Smad2/3 signaling pathway

Diabetic cardiomyopathy (DCM) is one of the main causes of heart failure in patients with diabetes. Cardiac fibrosis caused by endothelial mesenchymal transformation (EndMT) plays an important role in the pathogenesis of DCM. NLRC5 is a recently discovered immune and inflammatory regulatory molecule in the NOD-like receptor family, and is involved in organ fibrosis. In this study, we found that the expression of NLRC5 was up-regulated in endothelial cells (ECs) and cardiac fibroblasts (CFs) in diabetes models both in vivo and in vitro. NLRC5 knockdown significantly inhibited high glucose-induced EndMT. In addition, NLRC5 deficiency inhibited the expression of phosphorylated Smad2/3 and the activation of EndMT-related transcription factors in ECs induced by high glucose. However, the effect of NLRC5 deficiency on CFs was not obvious. In summary, our results suggest that NLRC5 deficiency ameliorates cardiac fibrosis in DCM by inhibiting EndMT through Smad2/3 signaling pathway and related transcription factors. NLRC5 is likely to be a biomarker and therapeutic target of cardiac fibrosis in diabetic cardiomyopathy.

458-P: Resveratrol Attenuates Diabetic Cardiomyopathy by Inhibiting Asymmetric Dimethylarginine-Induced PGC-1a Acetylation

The cardiac protection of resveratrol may due to improvement of mitochondrial function through SIRT1 activation and PGC-1α deacetylation. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is associated with diabetic cardiovascular complications and reported to have cross-talk with lysine acetylation in cells. This study was to determine the role of ADMA in the pathogenesis of diabetic cardiomyopathy, whether resveratrol could revise ADMA-induced pathological changes and elucidate the underlying mechanisms in rat model of type 2 diabetes mellitus (T2DM). Resveratrol was orally administered (50mg/kg/d) to T2DM rats for 16w. Echocardiography was performed to detect cardiac function. Contents of myocardial ATP and mitochondrial DNA were measured to evaluate mitochondrial function and biogenesis. Elevated endogenous ADMA content and its signal disorders were associated with cardiac and mitochondrial dysfunction in the myocardium of T2DM rats compared with control rats. Treatment with resveratrol significantly attenuated endogenous ADMA accumulation and cardiac dysfunction, increased myocardial mitochondrial DNA and ATP contents, as well as upregulated PGC-1α expression in the myocardium of resveratrol-treated diabetic rats compared with untreated diabetic rats. A positive feedback was observed in vitro that elevated ADMA return promoting its synthetic enzyme PRMT1 expression, reducing its metabolic enzymes DDAH2 expression, reproducing myocardial hypertrophy and mitochondrial dysfunction. Resveratrol treatment could reverse these pathological changes. More importantly, ADMA could enhance PGC-1α acetylation and reduced SIRT1 expressions, all of which were antagonized by resveratrol in cardiomyocytes. These results suggest that ADMA-induced PGC-1α hyperacetylation may serve as potential therapeutic targets for resveratrol to improve diabetic cardiomyopathy.

Echocardiographic Diagnosis of Diabetic Cardiomyopathy

Heart failure is common in the diabetic population, but while diabetic cardiomyopathy can cause heart failure, it is underestimated. Hyperglycemia, dyslipidemia and inflammation in diabetes are thought to play key roles in the pathogenesis of diabetic cardiomyopathy. Echocardiography has been the optimal noninvasive imaging test to evaluate the presence of cardiac dysfunction and it can provide clues to detect diabetic cardiomyopathy. This review discusses the echocardiographic findings of diabetic cardiomyopathy. Keywords: Diabetic cardiomyopathy; Heart failure; Diabetes mellitus; Echocardiography 중심 단어: 당뇨병성 심근병증; ì‹¬ë¶€ì „; 당뇨병; 심초음파

SAT-620 Left Ventricular Myocardial Deformation in T2DM Is Associated with Chronic Hyperglycemia but Not Myocardial Perfusion: A Study Based on Magnetic Resonance Imaging

Background: Diabetic cardiomyopathy is accompanied by left ventricular diastolic dysfunction. Abnormal glucose metabolism plays an important role in the pathogenesis of diabetic cardiomyopathy. However, it’s still not clear whether the influence of hyperglycemia on LV dysfunction is directly affects cardiomyocytes or is related to impaired myocardial perfusion. In this work, we focus on investigating the association between HbA1c and myocardial dysfunction, and if it is independent of myocardial perfusion reserve. Materials and Methods: 64 type 2 diabetic patients were recruited at the endocrine clinic. They are divided into two group, well blood glucose-controlled group (HbA1c<7) and poor glucose-controlled group (HbA1c≥7) T2DM group, according to their HbA1c level. All of the T2DM patients and age-matched healthy volunteers (normal glucose metabolism group, NGM group) underwent CMR to acquire normal values for myocardial strain and perfusion reserve. Results: Well blood glucose-controlled group owned lower global circumferential PSSR than NGM group (p=0.037). Global circumferential PS (p=0.011), global longitudinal PS (p=0.004), global radial PDSR (p=0.005), circumferential PDSR (p=0.001), longitudinal PDSR (p=0.001), global circumferential PSSR (p=0.049), longitudinal PSSR (p=0.041) were significantly lower in the poor glucose-controlled group compared to the NGM group. In the multivariable linear regression analysis, HbA1c existed in all equations except the global circumferential PSSR equation and p<0.05, and Slope, Max SI and Tpeak did not show dependent association with longitudinal and circumferential strain parameters. Conclusion: In subclinical cardiac dysfunction T2DM patients, diastolic dysfunction is more common, but systolic dysfunction is still exist. Poor blood glucose control which is defined as HbA1c ≥ 7% is an independent risk factor for LV deformation for T2DM patients. Subclinical myocardial dysfunction is not triggered by myocardial perfusion reserve.

Bioactive Compounds in Diabetic Cardiomyopathy: Current Approaches and Potential Diagnostic and Therapeutic Targets.

Diabetic Cardiomyopathy (DCM) has an adverse effect on health and occurs with or without concurrent vascular disease. Although several pathological mechanisms have been implicated in DCM, oxidative stress is widely thought to be the foremost cause for DCM pathogenesis. In this review, we focused on the role of bioactive compounds from different sources such as plant and marine products in cardiomyopathy. Natural Products (NPs) and their constituents were traditionally considered implausible as therapeutic agents. In the last few decades, studies on the use of NPs in the pharmaceutical field have reduced due to problems such as the requirement of compatibility of conventional NP extract libraries with high-throughput selection. The characteristics of NP structures such as high chemical variety, biochemical specificity, and other molecular properties that make them favorable as direct structures for drug synthesis and that distinguish them from combinatorial and synthetic compound libraries have been documented since ancient times. Consequently, the aim of this review was to provide an overview on the recent progress and development of bioactive compounds in DCM and to focus on the cellular mechanisms underlying cardiomyocyte dysfunction in their therapeutic targets.

Can We Prevent Mitochondrial Dysfunction and Diabetic Cardiomyopathy in Type 1 Diabetes Mellitus? Pathophysiology and Treatment Options.

Type 1 diabetes mellitus is a disease involving changes to energy metabolism. Chronic hyperglycemia is a major cause of diabetes complications. Hyperglycemia induces mechanisms that generate the excessive production of reactive oxygen species, leading to the development of oxidative stress. Studies with animal models have indicated the involvement of mitochondrial dysfunction in the pathogenesis of diabetic cardiomyopathy. In the current review, we aimed to collect scientific reports linking disorders in mitochondrial functioning with the development of diabetic cardiomyopathy in type 1 diabetes mellitus. We also aimed to present therapeutic approaches counteracting the development of mitochondrial dysfunction and diabetic cardiomyopathy in type 1 diabetes mellitus.

Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy.

Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin–angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.

Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence.

The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.

Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is a result of diabetes-induced changes in the structure and function of the heart. Hyperglycemia affects multiple pathways in the diabetic heart, but excessive reactive oxygen species (ROS) generation and oxidative stress represent common denominators associated with adverse tissue remodeling. Indeed, key processes underlying cardiac remodeling in diabetes are redox sensitive, including inflammation, organelle dysfunction, alteration in ion homeostasis, cardiomyocyte hypertrophy, apoptosis, fibrosis, and contractile dysfunction. Extensive experimental evidence supports the involvement of mitochondrial ROS formation in the alterations characterizing the diabetic heart. In this review we will outline the central role of mitochondrial ROS and alterations in the redox status contributing to the development of diabetic cardiomyopathy. We will discuss the role of different sources of ROS involved in this process, with a specific emphasis on mitochondrial ROS producing enzymes within cardiomyocytes. Finally, the therapeutic potential of pharmacological inhibitors of ROS sources within the mitochondria will be discussed.

Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR-141-mediated NLRP3 inflammasome and TGF-β1/Smads signaling in diabetic cardiomyopathy.

Melatonin is a hormone produced by the pineal gland, and it has extensive beneficial effects on various tissue and organs; however, whether melatonin has any effect on cardiac fibrosis in the pathogenesis of diabetic cardiomyopathy (DCM) is still unknown. Herein, we found that melatonin administration significantly ameliorated cardiac dysfunction and reduced collagen production by inhibiting TGF-β1/Smads signaling and NLRP3 inflammasome activation, as manifested by downregulating the expression of TGF-β1, p-Smad2, p-Smad3, NLRP3, ASC, cleaved caspase-1, mature IL-1β, and IL-18 in the heart of melatonin-treated mice with diabetes mellitus (DM). Similar beneficial effects of melatonin were consistently observed in high glucose (HG)-treated cardiac fibroblasts (CFs). Moreover, we also found that lncRNA MALAT1 (lncR-MALAT1) was increased along with concomitant decrease in microRNA-141 (miR-141) in DM mice and HG-treated CFs. Furthermore, we established NLRP3 and TGF-β1 as target genes of miR-141 and lncR-MALAT1 as an endogenous sponge or ceRNA to limit the functional availability of miR-141. Finally, we observed that knockdown of miR-141 abrogated anti-fibrosis action of melatonin in HG-treated CFs. Our findings indicate that melatonin produces an antifibrotic effect via inhibiting lncR-MALAT1/miR-141-mediated NLRP3 inflammasome activation and TGF-β1/Smads signaling, and it might be considered a potential agent for the treatment of DCM.

Hydrogen Sulfide Attenuates High Glucose-induced Myocardial Injury in Rat Cardiomyocytes by Suppressing Wnt/beta-catenin Pathway.

Diabetic cardiomyopathy (DCM) is one of the major heart complications of diabetic patients. Hydrogen sulfide (H2S) is now recognized as an important signaling molecule and has been shown to attenuate the development of diabetic cardiomyopathy. However, the underlying mechanisms linking H2S and the development of DCM have not been fully elucidated. In the present study, we therefore sought to explore the role and mechanism of H2S in the pathogenesis of DCM by establishing high glucose-induced injury model in neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Using cystathionine gamma-lyase (CSE) overexpression and CSE interference vectors transfection, the cell viability, cell apoptosis. and oxidative stress were determined and compared between the treatment of high glucose induction and exgenous NaHS administration. Meanwhile, the relationship between the CSE/H2S system and Wnt/beta-catenin pathway was analyzed and discussed in the high glucose-induced cardiomyocytes. Our results indicated that H2S played an important protective role in high glucose-induced apoptosis and oxidative stress in cardiomyocytes, as shown by the decreased reactive oxygen species and malondialdehyde levels, and the increased activities of superoxide dismutase, catalase and glutathione peroxidase. Moreover, H2S could attenuate the Wnt/β-catenin signalling pathway and up-regulate the expression of haem oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the diabetic myocardium cells. Together, these results demonstrated that H2S could attenuate high glucose-induced myocardial injury in rat cardiomyocytes by suppressing Wnt/β-catenin pathway.

Lessons from the Trials for the Desirable Effects of Sodium Glucose Co-Transporter 2 Inhibitors on Diabetic Cardiovascular Events and Renal Dysfunction.

Recent large placebo-controlled trials of sodium glucose co-transporter 2 (SGLT2) inhibitors revealed desirable effects on heart failure (HF) and renal dysfunction; however, the mechanisms underlying these effects are unknown. The characteristic changes in the early stage of diabetic cardiomyopathy (DCM) are myocardial and interstitial fibrosis, resulting in diastolic and subsequent systolic dysfunction, which leads to clinical HF. Pericytes are considered to play crucial roles in myocardial and interstitial fibrosis. In both DCM and diabetic retinopathy (DR), microaneurysm formation and a decrease in capillaries occur, triggered by pericyte loss. Furthermore, tubulointerstitial fibrosis develops in early diabetic nephropathy (DN), in which pericytes and mesangial cells are thought to play important roles. Previous reports indicate that pericytes and mesangial cells play key roles in the pathogenesis of DCM, DR and DN. SGLT2 is reported to be functionally expressed in pericytes and mesangial cells, and excessive glucose and Na+ entry through SGLT2 causes cellular dysfunction in a diabetic state. Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature.

Effects and mechanisms of PSS-loaded nanoparticles on coronary microcirculation dysfunction in streptozotocin-induced diabetic cardiomyopathy rats

Coronary microvascular dysfunction (CMD) is the pathological basis and pathogenesis of diabetic cardiomyopathy (DCM). Propylene glycol alginate sodium sulfate (PSS) as heparinoid drug has many biological activities. Here, a novel PSS-loaded nanoparticle (PSS-NP) was prepared to study its effect on the CMD of DCM. We used diabetes mellitus rat induced by STZ to establish the CMD model of DCM, and the study was detected by echocardiography, histological analysis, transmission electron microscopy, immunofluorescence staining, enzyme-linked immunosorbent assay, real time-PCR analysis, liquid-chip analysis, western blot analysis and so on. The experimental results suggested that PSS-NP could improve the survival state of rats, cardiac function, myocardial morphology and coronary microcirculation structure disorders, and increase the number of microvessels. In addition, we demonstrated that PSS-NP could alleviate the CMD by improving endothelial function, anticoagulation and antioxidative stress. The outcomes of this study provided new treatment thoughts for the therapy of coronary microcirculation dysfunction in DCM.

Bile Acids and Farnesoid X Receptor: Novel Target for the Treatment of Diabetic Cardiomyopathy.

Diabetes mellitus (DM) has become an increasingly common disease with high disability and mortality rates. Diabetes complications are the main cause of diabetes death and about 50% of diabetic patients died from heart disease in developed countries reported by World Health Organization. Diabetic cardiomyopathy (DCM) has been considered as a high incidence and serious complication of DM and plays a key role in the incidence and development of diabetes related heart failure. Metabolism dysregulation is regarded as an important and earlier factor occurred in the pathogenesis of DCM. Insulin resistance, oxidative stress, inflammation and mitochondrial dysfunction also contribute to the development of DCM. Farnesoid X Receptor (FXR) is a member of nuclear receptor superfamily, and plays a critical role in regulating lipid and glucose metabolism, oxidative stress and inflammation. FXR is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid and synthetic agonists such as obeticholic acid. BAs are the main active ingredients of many natural products and traditional medicines, especially bile or gallstones in animals, such as calculus bovis. Due to the regulatory effect of FXR on glucose and lipid metabolism, oxidative stress and inflammation, the treatment of BAs and FXR agonists for metabolic syndrome and DCM have gained more attention. This review will focus on the pathogenesis of diabetic cardiomyopathy and the regulatory effect of BAs and FXR on DCM.

FMK, an Inhibitor of p90RSK, Inhibits High Glucose-Induced TXNIP Expression via Regulation of ChREBP in Pancreatic β Cells.

Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell function, and apoptosis. TXNIP (Thioredoxin-interacting protein) is a key mediator of diabetic β-cell apoptosis and dysfunction in diabetes, and thus, its regulation represents a therapeutic target. Recent studies have reported that p90RSK is implicated in the pathogenesis of diabetic cardiomyopathy and nephropathy. In this study, we used FMK (a p90RSK inhibitor) to determine whether inhibition of p90RSK protects β-cells from chronic HG-induced TXNIP expression and to investigate the molecular mechanisms underlying the effect of FMK on its expression. In INS-1 pancreatic β-cells, HG-induced β-cell dysfunction, apoptosis, and ROS generation were significantly diminished by FMK. In contrast BI-D1870 (another p90RSK inhibitor) did not attenuate HG-induced TXNIP promoter activity or TXNIP expression. In addition, HG-induced nuclear translocation of ChREBP and its transcriptional target molecules were found to be regulated by FMK. These results demonstrate that HG-induced pancreatic β-cell dysfunction resulting in HG conditions is associated with TXNIP expression, and that FMK is responsible for HG-stimulated TXNIP gene expression by inactivating the regulation of ChREBP in pancreatic β-cells. Taken together, these findings suggest FMK may protect against HG-induced β-cell dysfunction and TXNIP expression by ChREBP regulation in pancreatic β-cells, and that FMK is a potential therapeutic reagent for the drug development of diabetes and its complications.

Role of Cytochrome p450 and Soluble Epoxide Hydrolase Enzymes and Their Associated Metabolites in the Pathogenesis of Diabetic Cardiomyopathy.

A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such as NPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of the DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J, and the decrease of cardioprotective EETs.