Prevention Of Diabetic Cardiomyopathy Research Articles

Fucoidan from Sargassum wightii reduces oxidative stress through upregulating Nrf2/HO-1 signaling pathway in alloxan-induced diabetic cardiomyopathy rats.

Diabetic cardiomyopathy (DCM) is a form of cardiac dysfunction caused by diabetes, increasing heart failure and death. Studies shown that hyperglycemia-induced oxidative stress significantly affects heart structure and functional changes during diabetic cardiomyopathy. Fucoidans are sulfated polysaccharide derived from naturally available seaweeds and reported for various biological functions such as antioxidant, anti-diabetic, and anti-inflammatory. However, the therapeutic potential of Indian seaweeds against DCM remains largely unexplored. Therefore, the current study aimed to work on the cardioprotective effect of extracted fucoidan from Sargassum wightii (SwF) in alloxan-induced DCM. Diabetes (DM) was induced with alloxan monohydrate (150mg/kg-1) dissolved in Nacl (0.9%) overnight-fasted rats. Group III, IV rats were DM induced, followed by treated with SwF (150mg/kg-1) and (300mg/kg-1). Group V and VI were non-diabetic rats and received SwF (150mg/kg-1) and (300mg/kg-1). SwF reduced classical progressive DM complications such as hyperglycemia, polydipsia, polyphagia, and polyurea in alloxan-induced diabetic rats. Biochemical analysis showed that SwF decreased blood glucose, cardiac markers enzymes, and lipid peroxidation levels compared to diabetic rats. SwF administration significantly increased Nrf2, HO-1, SOD, Catalase, and NQO1 gene expression. In addition, SwF-treated rats showed reduced heart tissue damage with increased Nrf2 and HO-1 protein expression. The current research concludes that targeting oxidative stress with SwF provided an effective role inthe prevention of DCM. Thus, fucoidan could be used to develop functional food ingredients for DCM.

The effect of eight weeks of high-intensity interval training and moderate-intensity continuous training on some factors causing oxidative stress in the cardiomyocytes of mice with type II diabetes

Background and aims: Diabetic cardiomyopathy (DCM) is a major cause of morbidity and mortality among diabetic patients. This study aimed to compare and investigate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on oxidative stress as one of the key links in the development of DCM in mice with type 2 diabetes mellitus (T2DM). Methods: Forty male C57BL/6J mice were randomly assigned to four groups of equal number (Control, T2DM, T2DM+HIIT, and T2DM+MICT). After the induction of T2DM, HIIT and MICT programs were conducted 5 days a week for 8 weeks. At the end of the experimental period, blood and heart samples were collected for subsequent measurements. Results: T2DM significantly up-regulated the levels of advanced glycation end products (AGEs, P=0.001) and the expression of 15-lipoxygenase (15-LOX, P=0.001) and 4-hydroxy-2-nonenal (4-HNE, P=0.001) compared to controlled mice. After 8 weeks of training, HIIT and MICT programs increased the levels of insulin (P<0.001) while reducing the levels of fasting blood glucose (P<0.001, P=0.024, respectively). On the other hand, it was found that HIIT and MICT programs significantly decreased the levels of AGEs (P<0.001), expression of 15-LOX (P=0.006, P=0.019, respectively), and 4-HNE (P=0.008 and P=0.035, respectively). Conclusion: Our findings revealed that exercise training, particularly MICT, will be highly helpful in the prevention of DCM through the improvement of glucose metabolism and reduction of 15-LOX expression.

Prevention of diabetic cardiomyopathy through metabolic amendments of myocardium by melatonin: a role beyond antioxidative efficiency

The alarming rise in diabetes throughout the world brings the scientist at the brink of finding a suitable compound that can impede glucotoxicity and insulin resistance involved development as well as progression of diabetes. Either devoid of insulin or resistance of cells to insulin brings forward the pancreatic tissue as the most vulnerably affected system. However, cardiac tissue, being the most exposed to circulation with high glucose content, is another target of hyperglycaemia. The remodelling of cardiac tissue in insulin resistant diabetic individuals includes cardiac hypertrophy along with misaligned diastolic and systolic functions. All these amendments cause declined cardiac contractility, the major indication of heart failure. The search for rationale behind such undesirable alterations put forward the involvement of altered cardiac metabolism in diabetes. Both carbohydrate and fatty acid metabolism have been found to be affected in diabetic individuals with declined glycolysis alongwith escalated lipolysis leading toward rise in fatty acid oxidation. Melatonin, with its antioxidative virtue prevents glucotoxicity induced excess reactive oxygen species (ROS) generation to afford protection to cellular systems. Nevertheless, the indole hinders ROS production by lowering both glucose and fatty acid accumulation through augmenting glycolysis along with diminishing lipolysis. Melatonin also expands its worth by keeping in order gluconeogenesis and glycogenesis pathways of metabolism in diabetic myocardium. The regulation of important metabolic pathways by melatonin in hyperglycaemic cardiac tissue assists the myocardium to maintain energy balance, the primary need for contractile behaviour. Hence, this review focuses on metabolic modulatory actions of melatonin in diabetic myocardium, which may encourage its usage as a saviour for diabetic cardiomyopathy.

Advanced Glycation End Product Blocker Drugs Have a Great Potential to Prevent Diabetic Cardiomyopathy in an Animal Model of Diabetes Mellitus Type-2.

Introduction Sphingosine 1 phosphate (S1P) is a product of the sphingosine kinase 1 (SphK1) enzyme. Increased S1P can lead to tissue fibrosis that is also one of the pathways for developing diabetic cardiomyopathy. Advanced glycation end products (AGEs) increase S1P in cells. The study is aimed at using aminoguanidine (AG) as an AGEs blocker drug to prevent diabetic cardiomyopathy. Materials and methods. 210 rats were enrolled in the study. Diabetes mellitus type-2 was induced, and rats were divided into AG treated diabetic and nondiabetic groups. The heart histology was assessed with Masson's trichrome and hematoxylin-eosin staining. Cardiac function was measured with transthoracic echocardiography. S1P level and SphK1 gene expression were measured by western-blot and RT-qPCR, respectively. Results Results showed that S1P level increases in diabetes, and its augmentation in cardiac tissue with K6PC-5 leads to cardiac fibrosis. 50 and 200 mg/kg of AG prevented cardiac fibrosis, but 100 mg/kg had no significant preventive effect. AG suppressed the SphK1 gene expression and reduced the fibrotic effect of S1P. AG preserved cardiac function by keeping ejection fraction and fractional shortening within the normal range in diabetic rats. Conclusion AG has a suppressor effect on SphK1 gene expression besides its AGEs blocker role. AG is a potential drug to use in diabetic patients for preventing the development of diabetic cardiomyopathy. Other drugs that have AGEs or S1P blocker effects are a good choice for diabetic cardiomyopathy prevention.

Amylin: new insight into pathogenesis, diagnosis, and prognosis of non-insulin-dependent diabetes-mellitus-related cardiomyopathy

Abstract Co-secretion with insulin, highly amyloidogenic human amylin is considered to contribute to the initiation and progression of diabetic heart complications, despite other situations such as hypertension and atherosclerosis. In response to insulin resistance, hyperinsulinemia, and consequently hyperamylinemia, is common in prediabetic patients, where highly concentrated amylin is prone to form amylin oligomers, which further assemble into fibrils and amyloids with high β-sheet content. The infusion and deposition of oligomeric amylin in myocytes cause a series of consequences, including cytosolic Ca2+ dysregulation, calmodulin activation, myocyte hypertrophy, and ventricular stiffness, eventually leading to heart failure. In this review, we present the latest reports of amylin-related heart complications, provide new insights, and state the underlying pathogenesis, diagnosis, possible treatment, and prevention of diabetic cardiomyopathy.

Krill Oil Inhibits NLRP3 Inflammasome Activation in the Prevention of the Pathological Injuries of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM), resulting in high mortality. Myocardial fibrosis, cardiomyocyte apoptosis and inflammatory cell infiltration are hallmarks of DCM, leading to cardiac dysfunction. To date, few effective approaches have been developed for the intervention of DCM. In the present study, we investigate the effect of krill oil (KO) on the prevention of DCM using a mouse model of DM induced by streptozotocin and a high-fat diet. The diabetic mice developed pathological features, including cardiac fibrosis, apoptosis and inflammatory cell infiltration, the effects of which were remarkably prevented by KO. Mechanistically, KO reversed the DM-induced cardiac expression of profibrotic and proinflammatory genes and attenuated DM-enhanced cardiac oxidative stress. Notably, KO exhibited a potent inhibitory effect on NLR family pyrin domain containing 3 (NLRP3) inflammasome that plays an important role in DCM. Further investigation showed that KO significantly upregulated the expression of Sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which are negative regulators of NLRP3. The present study reports for the first time the preventive effect of KO on the pathological injuries of DCM, providing SIRT3, PGC-1α and NLRP3 as molecular targets of KO. This work suggests that KO supplementation may be a viable approach in clinical prevention of DCM.

Inhibition of the long non-coding RNA ZFAS1 attenuates ferroptosis by sponging miR-150-5p and activates CCND2 against diabetic cardiomyopathy.

Diabetic cardiomyopathy (DbCM) is responsible for increased morbidity and mortality in patients with diabetes and heart failure. However, the pathogenesis of DbCM has not yet been identified. Here, we investigated the important role of lncRNA‐ZFAS1 in the pathological process of DbCM, which is associated with ferroptosis. Microarray data analysis of DbCM in patients or mouse models from GEO revealed the significance of ZFAS1 and the significant downregulation of miR‐150‐5p and CCND2. Briefly, DbCM was established in high glucose (HG)–treated cardiomyocytes and db/db mice to form in vitro and in vivo models. Ad‐ZFAS1, Ad‐sh‐ZFAS1, mimic miR‐150‐5p, Ad‐CCND2 and Ad‐sh‐CCND2 were intracoronarily administered to the mouse model or transfected into HG‐treated cardiomyocytes to determine whether ZFAS1 regulates miR‐150‐5p and CCND2 in ferroptosis. The effect of ZFAS1 on the left ventricular myocardial tissues of db/db mice and HG‐treated cardiomyocytes, ferroptosis and apoptosis was determined by Masson staining, immunohistochemical staining, Western blotting, monobromobimane staining, immunofluorescence staining and JC‐1 staining. The relationships among ZFAS1, miR‐150‐5p and CCND2 were evaluated using dual‐luciferase reporter assays and RNA pull‐down assays. Inhibition of ZFAS1 led to reduced collagen deposition, decreased cardiomyocyte apoptosis and ferroptosis, and attenuated DbCM progression. ZFAS1 sponges miR‐150‐5p to downregulate CCND2 expression. Ad‐sh‐ZFAS1, miR‐150‐5p mimic, and Ad‐CCND2 transfection attenuated ferroptosis and DbCM development both in vitro and in vivo. However, transfection with Ad‐ZFAS1 could reverse the positive effects of miR‐150‐5p mimic and Ad‐CCND2 in vitro and in vivo. lncRNA‐ZFAS1 acted as a ceRNA to sponge miR‐150‐5p and downregulate CCND2 to promote cardiomyocyte ferroptosis and DbCM development. Thus, ZFAS1 inhibition could be a promising therapeutic target for the treatment and prevention of DbCM.

Ketone Ester D-β-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice.

BackgroundHeart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus.Methods and ResultsType 2 diabetic (db/db) and their corresponding wild‐type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D‐β‐hydroxybutyrate‐(R)‐1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl‐CoA:3‐oxoacid‐CoA transferase and restored decreased expression of mitochondrial β‐hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP‐mediated oxygen consumption in cardiac mitochondria from both wild‐type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule‐associated protein 1 light chain 3–mediated autophagosome formation.ConclusionsModerate elevation in circulating D‐β‐hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.

Peroxiredomin-4 ameliorates lipotoxicity-induced oxidative stress and apoptosis in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM), one severe complication in the diabetes, leads to high mortality in the diabetic patients. However, the understanding of molecular mechanisms underlying DCM is far from completion. Herein, we investigated the disease-related differences in the proteomes of DCM based on db/db mice and verified the protective roles of peroxiredoxin-4 (Prdx4) in H9c2 cardiomyocytes treated by palmitic acid (PA). Fasting blood glucose (FBG) and cardiac function was detected in the 6-month-old control and diabetic mice. The hearts were then collected and analyzed by a coupled label-free and mass spectrometry approach. In vivo investigation indicated that body weight and FBG of db/db mice markedly increased, and diabetic heart exhibited obvious cardiac hypertrophy and lipid droplet accumulation, and cardiac dysfunction as is indicated by the increases of left ventricle posterior wall thickness in systole (LVPWd) and diastole (LVPWs), and reduction of fractional shortening (FS). We used proteomic analysis and then detected a grand total of 2636 proteins. 175 differentially expressed proteins (DEPs) were markedly detected in the diabetic heart. Thereinto, Prdx4 was markedly down-regulated in the diabetic heart. In vitro experiments revealed that 250 μM PA significantly inhibited viability of H9c2 cell. PA induced much accumulation of lipid droplet in cardiomyocytes and resulted in an increase of mRNA expressions of lipogenic genes (FASN and SCD1) and cardiac hypertrophic genes. Additionally, protein level of Prdx4 evidently reduced in the PA-treated H9c2 cell. It was further found that shRNA-mediated Prdx4 knockdown exacerbated PA-induced oxidative stress and cardiomyocyte apoptosis, whereas overexpressing Prdx4 in the H9c2 cells noteworthily limited PA-induced ROS generation and cardiomyocytes apoptosis. These data collectively reveal the essential role of abnormal Prdx4 in pathological alteration of DCM, and provide potentially therapeutic target for the prevention of DCM.

Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice.

To efficiently prevent diabetic cardiomyopathy (DCM), we have explored and confirmed that metallothionein (MT) prevents DCM by attenuating oxidative stress, and increasing expression of proteins associated with glucose metabolism. To determine whether Akt2 expression is critical to MT prevention of DCM, mice with either global Akt2 gene deletion (Akt2‐KO), or cardiomyocyte‐specific overexpressing MT gene (MT‐TG) or both combined (MT‐TG/Akt2‐KO) were used. Akt2‐KO mice exhibited symptoms of DCM (cardiac remodelling and dysfunction), and reduced expression of glycogen and glucose metabolism‐related proteins, despite an increase in total Akt (t‐Akt) phosphorylation. Cardiac MT overexpression in MT‐TG/Akt2‐KO mice prevented DCM and restored glucose metabolism‐related proteins expression and baseline t‐Akt phosphorylation. Furthermore, phosphorylation of ERK1/2 increased in the heart of MT‐TG/Akt2‐KO mice, compared with Akt2‐KO mice. As ERK1/2 has been implicated in the regulation of glucose transport and metabolism this increase could potentially underlie MT protective effect in MT‐TG/Akt2‐KO mice. Therefore, these results show that although our previous work has shown that MT preserving Akt2 activity is sufficient to prevent DCM, in the absence of Akt2 MT may stimulate alternative or downstream pathways protecting from DCM in a type 2 model of diabetes, and that this protection may be associated with the ERK activation pathway.

The triterpene, methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA3), attenuates high glucose-induced oxidative damage and apoptosis by improving energy metabolism

BackgroundHyperglycemia-induced cardiovascular dysfunction has been linked to oxidative stress and accelerated apoptosis in the diabetic myocardium. While there is currently no treatment for diabetic cardiomyopathy (DCM), studies suggest that the combinational use of anti-hyperglycemic agents and triterpenes could be effective in alleviating DCM. HypothesisTo investigate the therapeutic effect of methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA3), in the absence or presence of the anti-diabetic drug, metformin (MET), against hyperglycemia-induced cardiac injury using an in vitro H9c2 cell model. MethodsTo mimic a hyperglycemic state, H9c2 cells were exposed to high glucose (HG, 33 mM) for 24 h. Thereafter, the cells were treated with RA3 (1 μM), MET (1 μM) and the combination of MET (1 μM) plus RA3 (1 μM) for 24 h, to assess the treatments therapeutic effect. ResultsBiochemical analysis revealed that RA3, with or without MET, improves glucose uptake via insulin-dependent (IRS-1/PI3K/Akt signaling) and independent (AMPK) pathways whilst ameliorating the activity of antioxidant enzymes in the H9c2 cells. Mechanistically, RA3 was able to alleviate HG-stimulated oxidative stress through the inhibition of reactive oxygen species (ROS) and lipid peroxidation as well as the reduced expression of the PKC/NF-кB cascade through decreased intracellular lipid content. Subsequently, RA3 was able to mitigate HG-induced apoptosis by decreasing the activity of caspase 3/7 and DNA fragmentation in the cardiomyoblasts. ConclusionRA3, in the absence or presence of MET, demonstrated potent therapeutic properties against hyperglycemia-mediated cardiac damage and could be a suitable candidate in the prevention of DCM.

SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium–glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and renin–angiotensin–aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.

Resveratrol and Diabetic Cardiomyopathy: Focusing on the Protective Signaling Mechanisms.

Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetic mellitus that is characterized by diastolic disorder in the early stage and clinical heart failure in the later stage. Presently, DCM is considered one of the major causes of death in diabetic patients. Resveratrol (RSV), a naturally occurring stilbene, is widely reported as a cardioprotective substance in many heart diseases. Thus far, the specific roles of RSV in DCM prevention and treatment have attracted great attention. Here, we discuss the roles of RSV in DCM by focusing its downstream targets from both in vivo and in vitro studies. Among such targets, Sirtuins 1/3 and AMP-activated kinase have been identified as key mediators that induce cardioprotection during hyperglycemia. In addition, many other signaling molecules (e.g., forkhead box-O3a and extracellular regulated protein kinases) are also regulated in the presence of RSV and exert beneficial effects such as opposing oxidative stress, inflammation, and apoptosis in cardiomyocytes exposed to high-glucose conditions. The beneficial potential of an RSV/stem cell cotherapy is also reviewed as a promising therapeutic strategy for preventing the development of DCM.

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.

Assessment of the Preventive Effect Against Diabetic Cardiomyopathy of FGF1-Loaded Nanoliposomes Combined With Microbubble Cavitation by Ultrasound

Acidic fibroblast growth factor (FGF1) has great potential in preventing diabetic cardiomyopathy. This study aimed to evaluate the preventive effect of FGF1-loaded nanoliposomes (FGF1-nlip) combined with ultrasound-targeted microbubble destruction (UTMD) on diabetic cardiomyopathy (DCM) using ultrasound examination. Nanoliposomes encapsulating FGF1 were prepared by reverse phase evaporation. DM model rats were established by intraperitoneal injection of streptozotocin (STZ), and different forms of FGF1 (FGF1 solution, FGF1-nlip, and FGF1-nlip+UTMD) were used for a 12-week intervention. According to the transthoracic echocardiography and velocity vector imaging (VVI) indexes, the LVEF, LVFS, and VVI indexes (Vs, Sr, SRr) in the FGF1-nlip+UTMD group were significantly higher than those in the DM model group and other FGF1 intervention groups. From the real-time myocardial contrast echocardiography (RT-MCE) indexes, the FGF1-nlip+UTMD group A and A×β showed significant differences from the DM model group and other FGF1 intervention groups. Cardiac catheter hemodynamic testing, CD31 immunohistochemical staining, and electron microscopy also confirmed the same conclusion. These results confirmed that the abnormalities, including myocardial dysfunction and perfusion impairment, could be suppressed to different extents by the twice weekly FGF1 treatments for 12 consecutive weeks (free FGF1, FGF1-nlip, and FGF1-nlip+UTMD), with the strongest improvements observed in the FGF1-nlip+UTMD group. In conclusion, the VVI and RT-MCE techniques can detect left ventricular systolic function and perfusion changes in DM rats, providing a more effective experimental basis for the early detection and treatment evaluation of DCM, which is of great significance for the prevention of DCM.

470-P: Combined Use of Sulforaphane and Zinc Provides a Better Protection against Diabetic Cardiomyopathy than Either One Alone in Type 1 Diabetic OVE26 Mice

Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetic patients. Oxidative stress is considered to be one of the most important mechanisms. Thus, treatments targeting oxidative stress may represent suitable strategies for the effective prevention of DCM. Nuclear factor-E2-related factor 2 (Nrf2), a transcription factor responsible to oxidative stress, goes to nuclei and binds to antioxidant response elements of promoters of several antioxidant genes. Metallothionein (MT) is a protein that can bind heavy metal ions such as zinc (Zn) and also a potent scavenger of free radicals because of its high thiol contents. Genetically overexpressing either Nrf2 or MT specifically in the heart protects from DCM. In addition, we also showed that induction of MT with Zn or activation of Nrf2 with sulforaphane (SFN) also partially protects from DCM. Here we further explore whether up-regulation of both simultaneously with Zn and SFN combination would provide a better protection against DCM than either alone. OVE26 mouse is one genetic type 1 diabetic model with the diabetes onset at 3 weeks old and survival more than one year without insulin treatment, so it is very good model for diabetic complication study. 5-week old OVE26 mice were confirmed with hyperglycemia and then treated with SFN (0.5 mg/kg) and/or Zn (5 mg/kg) for 18 weeks. 23-week old OVE26 mice showed typical DCM, reflected by cardiac dysfunction and remodeling fibrosis by echocardiography and collagen staining, along significantly oxidative damage, and inflammatory responses using western blotting and real-time PCR. Treatment of OVE26 mice either with SFN or Zn significantly prevented the development of DCM, along with up-regulating Nrf2 function and overexpressing MT protein, respectively, but the best protection from DCM is in the SFN/Zn group. Therefore, combined use of SFN with Zn may provide a better protection against DCM than SFN or Zn alone for diabetic patients. Disclosure J. Wang: None. W. Wang: None. L. Cai: None. Funding American Diabetes Association (1-15-BS-018, 1-18-IBS-082 to L.C.)

Genome Wide Microarray Profiling Identified Differentially Expressed Circulating Biomarkers Associated with Early Development of Diabetic Cardiomyopathy

IntroductionCirculating long noncoding RNAs (lncRNAs) are emerging as valuable biomarkers in numerous diseases. However the expression signature of circulating lncRNAs is yet to be identified in diabetic cardiomyopathy (DCM). We used computational and system biology approach to predict circulating lncRNAs using plasma RNA before and after DCM.HypothesisWe hypothesized that lncRNAs could serve as blood‐based prognostic and diagnostic biomarkers in DCM detection.MethodsThe left ventricular function was measured with echocardiography in control and db/db mice. Expression profiling of lncRNAs was performed using LncRNA Array v3.0 (8 × 60K, Arraystar).ResultsA total of 17,124 lncRNAs and 13,333 mRNAs were profiled of which 814 lncRNAs and 2707 mRNAs were deregulated, and more than half were intergenic lncRNAs and antisense lncRNAs. Ten dysregulated plasma lncRNAs were validated by quantitative PCR assays. For the gene ontologies related to plasma, the enrichment was observed for those mRNAs which were found to be significantly co‐expressed with the neighboring lncRNAs during DCM. Bioinformatics analysis revealed that the altered lncRNAs regulated the differentially expressed mRNAs which were profoundly enriched for pathways such as insulin signaling, fatty acid metabolism, MAPK signaling, and hypertrophy cardiomyopathy which in the past has been associated with diabetic pathogenesis. To evaluate the translational efficiency of our mouse model, we experimentally validated the results using human induced pluripotent cell‐derived cardiomyocytes (hiPSCs‐CMs) for the in vitro DCM model. We found that most of the gene expression patterns were repeated in hiPSCs‐CMs and several of these lncRNAs genes have been associated with DCM in the past.ConclusionCirculating lncRNAs are dysregulated in DCM, and our results depict the changing transcriptome as a function of disease progression and functional role of lncRNAs. These lncRNAs may serve as promising targets for DCM prevention, early diagnosis, and therapy.Support or Funding InformationThis work was supported, in part, by a National Institutes of Health research grant P01GM 066730 (to Dr. Bosnjak) from the United States Public Health Services, Bethesda, Maryland, USA. The funding body had no role in the design of the study, collection, analysis, and interpretation of data, and in writing the abstract.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Early Detection and Prevention of Diabetic Cardiomyopathy in Pediatric Age Group

Type 1 diabetes mellitus (DM) is one of the most common chronic diseases in children with long-term serious complications including cardiac impairment that constitutes one of the most common causes of death in these children. Diabetes is a major risk factor for cardiovascular disease (CVD) including the cardiac muscle, causing both systolic and diastolic cardiac dysfunction. The etiology of the diabetes- associated cardiovascular morbidity and mortality is not completely clear [1].

Diabetes mellitus and heart failure: insights from a toxic relationship

Diabetes mellitus and heart failure: insights from a toxic relationship

Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis

Elevated tumor suppressor p53 expression has been associated with heart diseases, including the diabetic heart. However, its precise role in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. We hypothesized that the development of DCM is attributed to up-regulated p53-mediated both early cardiac cell death and persistent cell senescence, glycolytic and angiogenetic dysfunctions. The present study investigated the effect of p53 inhibition with its specific inhibitor pifithrin-α (PFT-α) on the pathogenesis of DCM and its associated mechanisms. Type 1 diabetes was induced with multiple low doses of streptozotocin. Both hyperglycemic and age-matched control mice were treated with and without PFT-α five times a week for 2 months and then sacrificed at 3 and 6 months post-diabetes. Treatment with PFT-α significantly prevented the progression of diabetes-induced cardiac remodeling and dysfunction (i.e., DCM). Mechanistically, the inhibition of p53 prevented the cardiac apoptosis during early-stage diabetes (0.5 month), attenuated diabetes-induced cell senescence (3 and 6 months), and improved both glycolytic and angiogenic defects by increasing hypoxia-induced factor (HIF)-1α protein stability and upregulating HIF-1α transcription of specific target genes at 3 and 6 months after diabetes. Therefore, the targeted inhibition of p53 in diabetic individuals may provide a novel approach for the prevention of DCM.