Pathogenesis Of Diabetic Cardiomyopathy Research Articles

HEART FAILURE AND DIABETES MELLITUS: SELECTED ISSUES OF ETIOLOGY AND PATHOGENESIS, PROGNOSIS AND TREATMENT

This review is devoted to the study of issues relating to the features of associated course of chronic heart failure (CHF) and diabetes mellitus (DM). The modern views on the epidemiology, pathogenesis of DM and CHF are systematized. The pathogenesis of diabetic cardiomyopathy is described in details. The results of the well-known studies that show the negative impact of DM on CHF prognosis are presented. The principles of CHF pathogenetic therapy in patients with DM including the role of neurohormonal modulators are analyzed. The results of multicenter studies in patients with CHF and concomitant DM type 2 show that almost all first-line drugs recommended for CHF treatment are effective in patients with DM.

Glucagon-like peptide-1 protects cardiomyocytes from advanced oxidation protein product-induced apoptosis via the PI3K/Akt/Bad signaling pathway.

Cardiomyocyte apoptosis is a major event in the pathogenesis of diabetic cardiomyopathy. Currently, no single effective treatment for diabetic cardiomyopathy exists. The present study investigated whether advanced oxidative protein products (AOPPs) have a detrimental role in the survival of cardiomyocytes and if glucagon-like peptide-1 (GLP-1) exerts a cardioprotective effect under these circumstances. The present study also aimed to determine the underlying mechanisms. H9c2 cells were exposed to increasing concentrations of AOPPs in the presence or absence of GLP-1, and the viability and apoptotic rate were detected using a cell counting kit-8 assay and flow cytometry, respectively. In addition, a phosphatidylino-sitol-4,5-bisphosphate 3-kinase (PI3K) inhibitor, LY294002, was employed to illustrate the mechanism of the antiapoptotic effect of GLP-1. The expression levels of the apoptotic-associated proteins, Akt, B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter (Bad), Bcl-2-associated X protein (Bax) and caspase-3 were measured by western blotting. It was revealed that GLP-1 significantly attenuated AOPP-induced cell toxicity and apoptosis. AOPPs inactivated the phosphorylation of Akt, reduced the phosphorylation of Bad, decreased the expression of Bcl-2, increased the expression of Bax and the activation of caspase-3 in H9c2 cells. GLP-1 reversed the above changes induced by AOPPs and the protective effects of GLP-1 were abolished by the PI3K inhibitor, LY294002. In conclusion, the present data suggested that GLP-1 protected cardiomyocytes against AOPP-induced apoptosis, predominantly via the PI3K/Akt/Bad pathway. These results provided a conceivable mechanism for the development of diabetic cardiomyopathy and rendered a novel application of GLP-1 exerting favorable cardiac effects for the treatment of diabetic cardiomyopathy.

Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy

AimsThe mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy. MethodsThe mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured. ResultsIncubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation. ConclusionsTherapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.

Abstract 13631: Therapeutic Inhibition of Mitochondrial Reactive Oxygen Species With Mito-tempo Reduces Diabetic Cardiomyopathy

Introduction: The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production and subsequent oxidative damage have been implicated in the pathogenesis of diabetic cardiomyopathy. We hypothesized that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in diabetic cardiomyopathy. Hypothesis: We hypothesized that therapeutic inhibition of mitochondrial ROS with mito-TEMPO reduces diabetic cardiomyopathy. Methods: The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin (STZ)-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and single mitochondrial superoxide generation and cell death were measured. Results: Incubation with high glucose increased mitochondria superoxide generation in cultured adult cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO also abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular ROS formation and oxidative damage were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular ROS formation and oxidative damage, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts without change of blood glucose, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Mechanistic study revealed that the protective effects of mito-TMEPO were associated with down-regulation of ERK1/2 phosphorylation in diabetic hearts and high glucose-stimulated cardiomyocytes. Conclusions: Therapeutic inhibition of mitochondrial ROS by mitochondria-targeted antioxidant mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in both type-1 and type-2 diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.

Correlation between advanced glycation end-products and the expression of fatty inflammatory factors in type II diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is one of the most severe complications of diabetes without a clear pathogenesis. Th is study investigated the adiponectin (APN) and leptin levels in type II DCM, as well as their correlation with advanced glycation end-products (AGEs). From 2011-2013, 78 type II diabetes mellitus (T2DM) cases (40-65 years old) in the Taian region were randomly selected. Based on the results of colour Doppler ultrasonography and coronary angiography, the cases were divided into a simple T2DM group (40 cases) and a DCM group (38 cases). Forty healthy subjects were used as normal control (NC). An enzyme-linked immunosorbent assay was performed to determine the levels of fa tty inflammatory factors such as APN, leptin and AGEs, and a correlation analysis was conducted. In the T2DM group, the APN levels were decreased but the leptin and AGE levels were significantly increased compared to the NC group. In the DCM group, the APN levels were decreased but the leptin and AGE levels were significantly increased (P<0.01) compared to the T2DM group. Th e AGE levels were positively correlated with disease progression and with fasting plasma glucose levels, glycated haemoglobin, insulin resistance and leptin, but were negatively correlated with APN levels. Additionally, the APN and leptin levels were independently related to the AGE levels. Fatty inflammatory factors play a significant role in the progression of both simple T2DM and DCM. Th e results of this study revealed the pathogenesis of DCM and indicated the potential significance of AGEs in DCM prevention and treatment.

Involvement of long noncoding RNA MALAT1 in the pathogenesis of diabetic cardiomyopathy

Involvement of long noncoding RNA MALAT1 in the pathogenesis of diabetic cardiomyopathy

GW26-e2443 Changes in gene expression of calreticulin in the myocardium of streptozotocin-induced diabetic cardiomyopathy

Calreticulin (CRT) is major Ca2+ -binding protein mainly resident in the endoplasmic reticulum (ER) lumen. Evidences showed it was associated with many cardiovascular diseases. However, whether CRT is involved in the pathogenesis of diabetic cardiomyopathy (DCM) is still unknown. Our aim was to

Abstract 21: Diabetic Ketoacidosis Compromises Cardiac Mitochondrial Quality Control in Humans

Mitochondrial injury plays a key role in the pathogenesis of diabetic cardiomyopathy, a risk factor for heart failure in diabetic populations. Dysfunctional mitochondria are eliminated through several coordinated mitochondrial quality control mechanisms including the autophagy-lysosome degradation pathway, a process termed mitophagy. Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of type 1 diabetes. We have shown that adolescents and young adults with uncomplicated DKA mount a robust systemic inflammatory response which is associated with diastolic cardiac abnormality. However, it remains unknown if cardiac abnormality in patients with DKA is correlated with altered mitochondrial quality control processes. In the present study, using immunofluorescent labeling and confocal microscopic imaging, we examined a series of proteins involved in autophagy, mitophagy and mitochondrial dynamics in paraffin-embedded autopsy heart tissues from young people without or with fatal DKA. We found that the expression levels of beclin 1, microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein (LAMP) 1/2 are not changed, but that of p62 is increased in the heart of DKA patients, suggesting a decreased autophagy. Also, the expression levels and localization of Pink1, parkin and Rab9, three potential regulators of mitophagy, are markedly changed, indicating an altered mitophagy in the DKA heart. In addition, mitochondrial fusion and fission proteins (Mitofusin 2, Opa1, Drp1 and Fis1) are all altered to varying degrees in the DKA heart, which is accompanied by increased mitochondrial fragmentation, oxidative injury and apoptosis (TUNEL positive cells). Together, these findings demonstrate that the mitochondrial quality control mechanisms are not operating normally in the heart of patients with DKA. Therefore, therapeutic strategies that aim to improve the efficiency of the mitochondrial quality control may have the potential to reduce diabetic cardiac injury and heart failure in young type 1 diabetic patients.

Rutin administration attenuates myocardial dysfunction in diabetic rats.

BackgroundOxidative stress plays a major role in diabetic cardiomyopathy pathogenesis. Anti-oxidant therapy has been investigated in preventing or treating several diabetic complications. However, anti-oxidant action on diabetic-induced cardiac remodeling is not completely clear. This study evaluated the effects of rutin, a flavonoid, on cardiac and myocardial function in diabetic rats.MethodsWistar rats were assigned into control (C, n = 14); control-rutin (C-R, n = 14); diabetes mellitus (DM, n = 16); and DM-rutin (DM-R, n = 16) groups. Seven days after inducing diabetes (streptozotocin, 60 mg/kg, i.p.), rutin was injected intraperitoneally once a week (50 mg/kg) for 7 weeks. Echocardiogram was performed and myocardial function assessed in left ventricular (LV) papillary muscles. Serum insulin concentration was measured by ELISA. Statistics: One-way ANOVA and Tukey’s post hoc test.ResultsGlycemia was higher in DM than DM-R and C and in DM-R than C-R. Insulin concentration was lower in diabetic groups than controls (C 2.45 ± 0.67; C-R 2.09 ± 0.52; DM 0.59 ± 0.18; DM-R 0.82 ± 0.21 ng/mL). Echocardiogram showed no differences between C-R and C. DM had increased LV systolic diameter compared to C, and increased left atrium diameter/body weight (BW) ratio and LV mass/BW ratio compared to C and DM-R. Septal wall thickness, LV diastolic diameter/BW ratio, and relative wall thickness were lower in DM-R than DM. Fractional shortening and posterior wall shortening velocity were lower in DM than C and DM-R. In papillary muscle preparation, DM and DM-R presented higher time to peak tension and time from peak tension to 50% relaxation than controls; time to peak tension was lower in DM-R than DM. Under 0.625 and 1.25 mM extracellular calcium concentrations, DM had higher developed tension than C.ConclusionRutin attenuates cardiac remodeling and left ventricular and myocardial dysfunction caused by streptozotocin-induced diabetes mellitus.

Metabolic abnormalities of the heart in type II diabetes.

Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and hypertension. Although the pathogenesis of diabetic cardiomyopathy has yet to be fully elucidated, aberrations in cardiac substrate metabolism and energetics are thought to be key drivers. These aberrations include excessive fatty acid utilisation and storage, suppressed glucose oxidation and impaired mitochondrial oxidative phosphorylation. An appreciation of how these abnormalities arise and synergise to promote adverse cardiac remodelling is critical to their effective amelioration. This review focuses on disturbances in myocardial fuel (fatty acids and glucose) flux and energetics in type 2 diabetes, how these disturbances relate to the development of diabetic cardiomyopathy and the potential therapeutic agents that could be used to correct them.

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed "mitophagy," is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically.

Rho Kinase Inhibition Improves Cardiac Cross‐Bridge Dynamics in Early Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) is associated with left ventricle fibrosis, hypertrophy and diastolic dysfunction. Cardiomyocyte subcellular alterations are thought to drive contractile dysfunction in early DCM. Rho kinase (ROCK) has been implicated in the pathogenesis of DCM and is known to interact with proteins in the actin-myosin cross-bridge (CB) that control myosin head extension. With the use of synchrotron radiation, we are able to examine CB dynamics in real time in the in situ beating heart. Thus, we aimed to determine if ROCK was involved in the pathogenesis of DCM. Cardiac CB dynamics and function were examined in control and diabetic rats treated a ROCK inhibitor (fasudil, 10mg/kg/day) or saline vehicle for two weeks, one week after the induction of diabetes. In the deeper subendocardial layer of the myocardium, diabetic rats had significantly reduced diastolic myosin head extension (p<0.05) compared to control rats. Fasudil treatment improved diastolic myosin head extension in the subendocardium of diabetic rats. Impaired CB function was associated with a trend for a 20% reduction in myosin binding protein C expression in diabetic rats compared to control rats, and fasudil treatment partially prevented this reduction in diabetic rats. Our results suggest ROCK may impair CB dynamics in early DCM by altering the phosphorylation of thick filament proteins.

EGFR inhibition protects the cardiac remodeling through attenuating oxidative stress in STZ‐induced diabetic mouse model

Background Diabetes mellitus is strongly associated with cardiomyopathy. The underlying mechanisms for the development of diabetic cardiomyopathy are complex and not totally resolved. Recent studies showed epidermal growth factor receptor(EGFR) has been involved in the diabetes-induced cardiac injury. However, there exists a paradox of the role of EGFR in diabetic heart. The aim of the present study is to further determine the role of EGRF in the pathogenesis of diabetic cardiomyopathy. Methods: C57BL/6J mice were injected with streptozotocin only or in combination with EGFR inhibitors (AG1478 and a new inhibitor 451) for 8 weeks. In vitro, cardiac H9C2 cells were treated by high glucose concentration (HGC) in the presence or absence of ERFR inhibitors. Results: In type 1 diabetes model, diabetes induced phospohorylation of EGFR and AKT, increased cardiac ROS level, and ultimately leaded to cardiac remodeling including cardiac hypertrophy, disorganization, apoptosis and fibrosis. Interestingly, all these molecular and pathological alterations were attenuated by the treatment with EGFR inhibitors. In vitro, similar results were also observed in cardiac cells exposed to HGC. In addition, the HGC-induced cardiomyocyte injuries were also significantly reduced by NAC, an inhibitor of ROS. Conclusion: This study further provides evidence for a detrimental role of EGFR in the pathogenesis of diabetic cardiomyopathy via activating ROS generation, and suggests that EGFR may be a potencial therapeutic target in treating diabetic cardiomyopathy.

Blockage of ROS and NF-κB-mediated inflammation by a new chalcone L6H9 protects cardiomyocytes from hyperglycemia-induced injuries

Increased oxidative stress and cardiac inflammation have been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). We previously found that a novel chalcone derivative, L6H9, was able to reduce LPS-induced inflammatory response in macrophages. This study was designed to investigate its protective effects on DCM and the underlying mechanisms. H9C2 cells were cultured with DMEM containing 33mmol/L of glucose in the presence or absence of L6H9. Pretreatment with L6H9 significantly reduced high glucose-induced inflammatory cytokine expression, ROS level increase, mitochondrial dysfunction, cell apoptosis, fibrosis, and hypertrophy in H9c2 cells, which may be mediated by NF-κB inhibition and Nrf2 activation. In mice with STZ-induced diabetes, oral administration of L6H9 at 20mg/kg/day for 8weeks significantly decreased the cardiac cytokine and ROS level, accompanied by decreasing cardiac apoptosis and hypertrophy, and, finally, improved histological abnormalities and fibrosis, without affecting the hyperglycemia. L6H9 also attenuated the diabetes-induced NF-κB activation and Nrf2 decrease in diabetic hearts. These results strongly suggest that L6H9 may have great therapeutic potential in the treatment of DCM via blockage of inflammation and oxidative stress. This study also provides a deeper understanding of the regulatory role of Nrf2 and NF-κB in DCM, indicating that they may be important therapeutic targets for diabetic complications.

Role of tissue transglutaminase in the pathogenesis of diabetic cardiomyopathy and the intervention effect of rutin

The aim of this study was to investigate the role of tissue transglutaminase (tTG) in the pathogenesis of diabetic cardiomyopathy (DCM) and the intervention effect of rutin. DCM was induced in rats by the injection of streptozotocin (STZ; 25 mg/kg). After a preliminary examination, the rats were randomly divided into four groups: Control (n=8), STZ-induced DCM (n=8), STZ + positive drug (captopril; n=6) and STZ + rutin (n=8) groups. The DCM model was evaluated using blood sugar values, serum enzyme levels, hematoxylin and eosin staining and Masson’s staining, ex vivo. The protein and mRNA expression of tTG was assessed with immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The rat model of DCM was successfully established by STZ administration, and the expression levels of tTG were significantly increased in the DCM model. Following the injection of captopril or rutin, the blood sugar values, collagen content and expression levels of tTG were gradually reduced and serum enzyme levels were increased, as compared with those in the STZ-induced DCM group. In conclusion, tTG plays an important role in STZ-induced DCM. In addition, rutin may inhibit the expression of tTG and regulate myocardial injury in STZ-induced DCM.

Irbesartan ameliorates diabetic cardiomyopathy by regulating protein kinase D and ER stress activation in a type 2 diabetes rat model

Recent studies demonstrate an important role of protein kinase D (PKD) in the cardiovascular system. However, the potential role of PKD in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. Irbesartan has beneficial effects against diabetes-induced heart damage, while the mechanisms were still poorly understood. Our present study was designed to investigate the effects of irbesartan in DCM and whether the cardioprotective effects of irbesartan were mediated by PKD and endoplasmic reticulum (ER) stress. We induced the type 2 diabetic rat model by high fat diet and low dose streptozotocin injection. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. 8-weeks administration of irbesartan (15, 30 and 45mg/kg/day) was used to evaluate the effect irbesartan in DCM. Diabetic rats revealed severe metabolic abnormalities, left ventricular dysfunction, myocardial fibrosis and apoptosis. PKD and ER stress were excessive activated in the myocardium of diabetic rats. Furthermore, cardiac fibrosis, apoptosis, diastolic dysfunction and ER stress were all significantly related to PKD activation in diabetic rats. Irbesartan treatment attenuated the activation of PKD and ER stress, which paralleled its cardioprotective effects. Our study suggests that irbesartan could ameliorate cardiac remodeling and dysfunction in type 2 diabetes, and these beneficial effects were associated with its ability to suppress the activation of PKD and ER stress.

Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress

Diabetic cardiomyopathy is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. However, the underlying molecular mechanisms that lead to its development have not been fully elucidated. Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that is critical for the regulation of cardiovascular homeostasis. Recently, therapeutic strategies aimed at increasing its levels have proven cardioprotective in models of acute myocardial ischemia–reperfusion injury and heart failure. The precise role of H2S in the pathogenesis of diabetic cardiomyopathy has not yet been established. Therefore, the goal of the present study was to evaluate circulating and cardiac H2S levels in a murine model of high fat diet (HFD)-induced cardiomyopathy. Diabetic cardiomyopathy was produced by feeding mice HFD (60% fat) chow for 24 weeks. HFD feeding reduced both circulating and cardiac H2S and induced hallmark features of type-2 diabetes. We also observed marked cardiac dysfunction, evidence of cardiac enlargement, cardiac hypertrophy, and fibrosis. H2S therapy (SG-1002, an orally active H2S donor) restored sulfide levels, improved some of the metabolic perturbations stemming from HFD feeding, and attenuated HFD-induced cardiac dysfunction. Additional analysis revealed that H2S therapy restored adiponectin levels and suppressed cardiac ER stress stemming from HFD feeding. These results suggest that diminished circulating and cardiac H2S levels play a role in the pathophysiology of HFD-induced cardiomyopathy. Additionally, these results suggest that H2S therapy may be of clinical importance in the treatment of cardiovascular complications stemming from diabetes.

Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy.

Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.

Cardiac H2S Generation Is Reduced in Ageing Diabetic Mice.

Aims. To examine whether hydrogen sulfide (H2S) generation changed in ageing diabetic mouse hearts. Results. Compared to mice that were fed tap water only, mice that were fed 30% fructose solution for 15 months exhibited typical characteristics of a severe diabetic phenotype with cardiac hypertrophy, fibrosis, and dysfunction. H2S levels in plasma, heart tissues, and urine were significantly reduced in these mice as compared to those in controls. The expression of the H2S-generating enzymes, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase, was significantly decreased in the hearts of fructose-fed mice, whereas cystathionine-β-synthase levels were significantly increased. Conclusion. Our results suggest that this ageing diabetic mouse model developed diabetic cardiomyopathy and that H2S levels were reduced in the diabetic heart due to alterations in three H2S-producing enzymes, which may be involved in the pathogenesis of diabetic cardiomyopathy.

Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy.

Hyperglycemia-induced inflammation and apoptosis have important roles in the pathogenesis of diabetic cardiomyopathy. We recently found that a novel curcumin derivative, C66, is able to reduce the high glucose (HG)-induced inflammatory response. This study was designed to investigate the protective effects on diabetic cardiomyopathy and its underlying mechanisms. Pretreatment with C66 significantly reduced HG-induced overexpression of inflammatory cytokines via inactivation of nuclear factor-κB in both H9c2 cells and neonatal cardiomyocytes. Furthermore, we showed that the inhibition of Jun NH2-terminal kinase (JNK) phosphorylation contributed to the protection of C66 from inflammation and cell apoptosis, which was validated by the use of SP600125 and dominant-negative JNK. The molecular docking and kinase activity assay confirmed direct binding of C66 to and inhibition of JNK. In mice with type 1 diabetes, the administration of C66 or SP600125 at 5 mg/kg significantly decreased the levels of plasma and cardiac tumor necrosis factor-α, accompanied by decreasing cardiac apoptosis, and, finally, improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. Thus, this work demonstrated the therapeutic potential of the JNK-targeting compound C66 for the treatment of diabetic cardiomyopathy. Importantly, we indicated a critical role of JNK in diabetic heart injury, and suggested that JNK inhibition may be a feasible strategy for treating diabetic cardiomyopathy.