Cardiac Function In Diabetic Cardiomyopathy Research Articles

Myricetin alleviates diabetic cardiomyopathy by regulating gut microbiota and their metabolites

BackgroundThe gut microbiota is involved in the pathogenesis of diabetic cardiomyopathy (DCM). Myricetin protects cardiac function in DCM. However, the low bioavailability of myricetin fails to explain its pharmacological mechanisms thoroughly. Research has shown that myricetin has a positive effect on the gut microbiota. We hypothesize that myricetin improves the development of DCM via regulating gut microbiota.MethodsDCM mice were induced with streptozotocin and fed a high-fat diet, and then treated with myricetin by gavage and high-fat diet for 16 weeks. Indexes related to gut microbiota composition, cardiac structure, cardiac function, intestinal barrier function, and inflammation were detected. Moreover, the gut contents were transplanted to DCM mice, and the effect of fecal microbiota transplantation (FMT) on DCM mice was assessed.ResultsMyricetin could improve cardiac function in DCM mice by decreasing cardiomyocyte hypertrophy and interstitial fibrosis. The composition of gut microbiota, especially for short-chain fatty acid-producing bacteria involving Roseburia, Faecalibaculum, and Bifidobacterium, was more abundant by myricetin treatment in DCM mice. Myricetin increased occludin expression and the number of goblet cells in DCM mice. Compared with DCM mice unfed with gut content, the cardiac function, number of goblet cells, and expression of occludin in DCM mice fed by gut contents were elevated, while cardiomyocyte hypertrophy and TLR4/MyD88 pathway-related proteins were decreased.ConclusionsMyricetin can prevent DCM development by increasing the abundance of beneficial gut microbiota and restoring the gut barrier function.

The high-intensity interval training (HIIT) and curcumin supplementation can positively regulate the autophagy pathway in myocardial cells of STZ-induced diabetic rats

ObjectiveTargeting autophagy is a new therapeutic strategy for the complications of diabetes,such as diabetic cardiomyopathy (DCM). During diabetes, increased or insufficient autophagic activity causes aberrations in cellular homeostasis. Regarding the conflicting and unclear results regarding the effect of HIIT and curcumin supplementation on the expression of genes associated to autophagy, this study aimed to assess whether 4-week high-intensity interval training (HIIT) and curcumin supplementation are able to influence the expression of autophagy-related genes in myocardial cells of diabetic rats.MethodsIn an experimental design, 24 male Wistar rats were randomly divided into 4 groups: non-diabetic control (NC), diabetic control (DC), diabetes + HIIT (D + HIIT), and diabetes + curcumin (D + CU). After HIIT program and curcumin treatment, the genes expression of autophagy pathway were assessed in the myocardium by real-time PCR Tanique.ResultsThe results indicated that the expression levels of ATG1, Beclin1, ATG5, and LAMP-2 genes were significantly reduced in the DC group compared to the NC group (p < 0.001). Following 4-week HIIT, the expression of Beclin1, ATG-5, and LAMP-2 improved considerably compared to the DC group (p < 0.001, p < 0.001, and p < 0.05, respectively). In addition, after 4 weeks of curcumin supplementation, the expression levels of ATG-5 and Beclin-1 were significantly improved compared to the DC group (p < 0.001, p < 0.05, respectively). It seems HIIT and curcumin supplementation can be an effective approach for inducing autophagy and improving cardiac function in DCM rats.However, HIIT seems more effective than curcumin in this regard.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats

The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced diabetes mellitus (DM) rats with normal diet (ND) or KD for 6 weeks. Histopathology, adenosine triphosphate measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-positron emission tomography was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats, ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1β, tumor necrosis factor-α, interleukin-1β, interleukin6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial adenosine triphosphate, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation.

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a prevalent complication in patients with diabetes, resulting in high morbidity and mortality. However, the molecular mechanisms of diabetic cardiomyopathy have yet to be fully elucidated. In this study, we investigated a novel target, NOX1, an isoform of superoxide-producing NADPH oxidase with key functional involvement in the pathophysiology of DCM. The DCM rat model was established by a high-fat diet combined with streptozotocin injections. DCM rats elicited myocardial fibrosis exacerbation, which was accompanied by a marked elevation of NOX1 expression in cardiac tissue. In particular, a specific NOX1 inhibitor, ML171, effectively decreased myocardial fibrosis and protected against cardiac dysfunction in DCM rats. Rat neonatal cardiac fibroblasts were incubated with high glucose (HG, 33 mM) as an in vitro model of DCM. We also observed that the expression of NOX1 was upregulated in HG-cultured cardiac fibroblasts. Silencing of NOX1 was found to attenuate myocardial fibrosis and oxidative stress in HG-induced cardiac fibroblasts. Furthermore, the upregulation of NOX1 by hyperglycemia induced activation of the TLR2/NF-κB pathway both in vitro and in vivo, whereas these effects were significantly attenuated with NOX1 gene silencing and further enhanced with NOX1 gene overexpression. In summary, we demonstrated that NOX1 induced activation of the TLR2/NF-κB pathway and increased reactive oxygen species production accumulation, which ultimately increased myocardial fibrosis and deteriorated cardiac function in diabetic cardiomyopathy. Our study revealed that NOX1 was a potential therapeutic target for DCM.

Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy.

One of the major complications of diabetes mellitus is diabetic cardiomyopathy. One of the mechanisms that initiates the irreversible deterioration of cardiac function in diabetic cardiomyopathy is mitochondrial dysfunction. Functionally impaired mitochondria result in greater levels of oxidative stress and lipotoxicity, both of which exacerbate mitochondrial damage. Mitochondrial health is constantly monitored by mitochondrial quality control mechanisms. Mitophagy selectively degrades damaged mitochondria, thereby maintaining the healthy pool of mitochondria and preserving myocardial function. Mitophagy in diabetic cardiomyopathy is mediated by multiple mechanisms in a time-dependent manner. Potential targets for the treatment of diabetic cardiomyopathy include increased oxidative stress, mitochondrial dynamics, and mitochondrial clearance. Thus, stimulation of mitophagy represents a promising strategy for the alleviation of diabetic cardiomyopathy.

Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

Rosmarinic acid ameliorated cardiac dysfunction and mitochondrial injury in diabetic cardiomyopathy mice via activation of the SIRT1/PGC-1α pathway

Mitochondrial injury plays an essential role in the pathogenesis of diabetic cardiomyopathy (DCM). Previous studies demonstrated that rosmarinic acid (RA) treatment prevented high glucose-induced mitochondrial injury in vitro. However, whether RA can ameliorate cardiac function by preventing mitochondrial injury in DCM is unknown. The SIRT1/PGC-1α pathway has emerged as an important regulator of metabolic control and other mitochondrial functions. The present study was undertaken to determine the effects of RA on mitochondrial and cardiac function in DCM as well as the involvement of the SIRT1/PGC-1α pathway. Our results revealed that RA improved cardiac systolic and diastolic function and prevented mitochondrial injury in DCM, as shown by the reduced blood glucose and lipid levels, increased mitochondrial membrane potential levels, improved adenosine triphosphate synthesis, and inhibited apoptosis (P < 0.05). Moreover, RA upregulated the expression of SIRT1 and PGC-1α in DCM mice and high glucose-treated H9c2 cardiomyocytes (P < 0.05). Further mechanistic studies in H9c2 cardiomyocytes revealed that suppression of SIRT1 by Sh-SIRT1 counteracted the effects of RA on high glucose-induced abnormal metabolism of glucose and lipids, oxidative stress and apoptosis (P < 0.05). Taken together, these data indicate that RA prevented mitochondrial injury and cardiac dysfunction in DCM mice, and the SIRT1/PGC-1α pathway mediated the protective effects of RA.

Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway.

BackgroundEndothelial-to-mesenchymal transition (EndMT) is an important source of myofibroblasts that directly affects cardiac function in diabetic cardiomyopathy (DCM) via an unknown underlying mechanism. Sirt6 is a member of the Sirtuin family of NAD(+)-dependent enzymes that plays an important role in glucose and fatty acid metabolism. In this study, we investigated whether Sirt6 participates in EndMT during the development of T2DM and the possible underlying regulatory mechanisms.MethodsEndothelium-specific Sirt6 knockout (Sirt6-KOEC) mice (C57BL/6 genetic background) were generated using the classic Cre/loxp gene recombination system. T2DM was induced in eight-week-old male mice by feeding with a high-fat diet for three weeks followed by i.p. injection with 30 mg/kg of streptozotocin. The weight, lipids profiles, insulin, food intake and water intake of experimental animals were measured on a weekly basis. Cardiac microvascular endothelial cells (CMECs) were obtained from adult male mice; the isolated cells were cultured with high glucose (HG; 33 mmol/L) and palmitic acid (PA; 500 μmol/L) in DMEM for 24 h, or with normal glucose (NG; 5 mmol/L) as the control.ResultsSirt6 expression is significantly downregulated in CMECs treated with HG+PA. Additionally, Sirt6-KOEC was found to worsen DCM, as indicated by aggravated perivascular fibrosis, cardiomyocyte hypertrophy, and decreased cardiac function. In vitro, Sirt6 knockdown exacerbated the proliferation, and migration of CMECs exposed to HG+PA. Mechanistically, Sirt6 knockdown significantly enhanced Notch1 activation in CMECs treated with HG+PA, whereas Notch1 adenoviral interference significantly blunted the effects of Sirt6 knockdown on CMECs.ConclusionThis study is the first to demonstrate that Sirt6 participates in EndMT via the Notch1 signaling pathway in CMECs stimulated with HG+PA. Therefore, the findings of this study suggest that Sirt6 could provide a potential treatment strategy for DCM.

Coriolus versicolor alleviates diabetic cardiomyopathy by inhibiting cardiac fibrosis and NLRP3 inflammasome activation.

Coriolus versicolor (CV) is a traditional medicine and food mushroom. Our previous study demonstrated that CV extract exhibited anti-hyperglycemia and anti-insulin resistance effects. However, the effect of CV on cardiac function in diabetic cardiomyopathy (DCM) remains unclear. Therefore, we aimed to investigate the effect of CV on cardiac function in diabetes mellitus (DM) rats. We found that the cardiac dysfunction of DM rats was markedly improved by CV extract treatment. CV extract administration significantly attenuated cardiac fibrosis in DM rats, which was accompanied by suppressed transforming growth factor beta 1 (TGF-β1)/Smad signaling as indicated by decreased levels of TGF-β1, p-Smad2, and p-Smad3 and increased Smad7 expression. Moreover, CV extract treatment significantly alleviated cardiac inflammation as shown by decreased levels of NLRP3 receptor, cleaved caspase-1, IL-1β, and IL-18 in DM rats at least partly due to the inhibition of the NF-κB. In addition, high-glucose treatment induced cardiac fibrosis and increased cardiac inflammation in cardiac fibroblast cells, but these effects were ameliorated by CV extract treatment. Therefore, we conclude that the protective effect of CV on DCM is associated with the suppression of TGF-β1/Smad signaling and attenuation of NLRP3 inflammasome activation, suggesting that CV extract may be a potential therapeutic agent for DCM.

(Pro)renin Receptor RNA Interference Silencing Attenuates Diabetic Cardiomyopathy Pathological Process in Rats.

(Pro)renin receptor (PRR) is a novel component of the renin-angiotensin system that has been demonstrated to be involved in cardiovascular diseases. Recent research reported that diabetic cardiomyopathy (DCM) may be accompanied by high expression of PRR, indicating that PRR may be a potential therapeutic target for DCM. However, the exact mechanisms of PRR in DCM have not been completely clarified. This study hypothesized that PRR is involved in the pathological progression of DCM and can exacerbate myocardial fibrosis and cardiac dysfunction. Inhibition of PRR expression may alleviate these pathological changes. In this study, in vivo experiments were performed in Wistar rats, and in vitro experiments were carried out in rat cardiac fibroblasts. After establishing an in vivo DCM model, the rats were divided into a control group, DCM group, adenovirus scrambled short hairpin RNA group, and adenovirus PRR short hairpin RNA group to observe further the effects of PRR RNA interference (RNAi) silencing on the pathogenesis of DCM. The results showed that PRR RNAi silencing decreased myocardial fibrosis and improved cardiac function in DCM. The study also observed the effects of PRR RNAi silencing on high glucose stimulated cardiac fibroblasts, and the results showed that PRR RNAi silencing inhibited the expression of type I collagen, type III collagen, and transforming growth factor beta. It was concluded that PRR plays a key role in the pathological progression of DCM and that inhibition of PRR expression achieved by specific PRR RNAi silencing offers a new therapeutic approach for DCM. The underlying mechanisms of these effects may be associated with the ERK signaling pathway and oxidative stress.

Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction.

Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms. HU308 was used for the selective activation of CB2. Bafilomycin A1 was used for the blockade of autophagy and compound C was used to inhibit AMPK signaling. An streptozotocin (STZ)-induced mice model and high glucose (HG)-challenged cardiomyocytes were applied for study. Cardiac function was detected by echocardiography and Western blot for the detection of autophagy-related and its signaling-related proteins. Transmission electron microscopy was used for the analysis of autophagosome number. Cell viability was detected by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. We found that activating CB2 by HU308 improved cardiac function in DCM as well as cell viability in cardiomyocytes under HG challenge, while the administration of bafilomycin A1 attenuated the protective effects. HU308 enhanced the level of autophagy in the heart tissues from DCM mice as well as cardiomyocytes under HG challenge. HU308 triggered the AMPK-mTOR-p70S6K signaling pathway, while the administration of compound C attenuated the cardio-protective effect of HU308 in cardiomyocytes under HG challenge. In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.

Resveratrol Ameliorates Cardiac Dysfunction by Inhibiting Apoptosis via the PI3K/Akt/FoxO3a Pathway in a Rat Model of Diabetic Cardiomyopathy

The aim of this study was to explore the effect and mechanism of action of resveratrol (RSV) on cardiac function in diabetic cardiomyopathy (DCM). Hyperglycemia-induced apoptosis contributes to the pathogenic changes in DCM. RSV treatment inhibited high glucose-induced apoptosis of neonatal rat ventricular myocytes. Additionally, high glucose decreased cell viability, prevented serine-threonine kinase (Akt) and FoxO3a phosphorylation, and suppressed cytoplasmic translocation of FoxO3a. However, these effects of apoptosis were reversed by 10 μM of RSV. The PI3K inhibitor LY294002 abolished the RSV protective effect in vitro. RSV (5 or 50 mg·kg·d orally for 8 weeks) prevented the deterioration of cardiac function and structural cardiomyopathy in a streptozotocin-induced rat model of diabetes and reduced apoptosis in diabetic myocardium. Furthermore, it restored streptozotocin-impaired phosphorylation of Akt and FoxO3a (p-Akt and p-FoxO3a) and suppressed nuclear translocation of FoxO3a in vivo. Together, these data indicate that RSV has therapeutic potential against DCM by inhibiting apoptosis via the PI3K/Akt/FoxO3a pathway.

Inhibiting microRNA-144 abates oxidative stress and reduces apoptosis in hearts of streptozotocin-induced diabetic mice.

Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to the development of diabetic cardiomyopathy. However, little is known about the role of microRNAs in the regulation of ROS formation and myocardial apoptosis in streptozotocin (STZ)-induced diabetic mice. It was observed that microRNA-144 (miR-144) level was lower in heart tissues of STZ-induced diabetic mice. High glucose exposure also reduced miR-144 levels in cultured cardiomyocytes. Moreover, miR-144 modulated high glucose-induced oxidative stress in cultured cardiomyocytes by directly targeting nuclear factor-erythroid 2-related factor 2 (Nrf2), which was a central regulator of cellular response to oxidative stress. The miR-144 mimics aggravated high glucose-induced ROS formation and apoptosis in cardiomyocytes, which could be attenuated by treatment with Dh404, an activator of Nrf2. Meanwhile, inhibition of miR-144 suppressed ROS formation and apoptosis induced by high glucose in cultured cardiomyocytes. What was more important is that reduced myocardial oxidative stress and apoptosis and improved cardiac function were identified in STZ-induced diabetic mice when treated with miR-144 antagomir. Although miR-144 cannot explain the increased oxidative stress in STZ, therapeutic interventions directed at decreasing miR-144 may help to decrease oxidative stress in these hearts. Inhibition of miR-144 might have clinical potential to abate oxidative stress as well as to reduce cardiomyocyte apoptosis and improve cardiac function in diabetic cardiomyopathy.

Quantitative stress echocardiography in pediatric patients with type-1 diabetes mellitus

s of the 51st Workshop for Pediatric Research 51st Workshop for Pediatric Research Gottingen, Germany 16-17 April 2015 This supplement has not been sponsored. Meeting abstracts Aims Type-1 diabetes mellitus (T1DM) is among the most common chronic diseases in children. Serious long-term complications include both ultra-morphologic and functional cardiac impairment. Whether these pathologic processes already take place in the early phase of T1DM yet has to be determined. Aim of this prospective, blinded, clinical study was to assess the effect of T1DM on left ventricular (LV) myocardial function in pediatric patients using quantitative stress echocardiography. Methods We included 40 patients with T1DM (aged 11.53 ± 3.1 years) and 44 sex-matched healthy controls (11.43 ± 2.9 years; p = 0.91). Conventional and quantitative echocardiography was performed both at rest and during physical exercise on a bicycle. Myocardial strain and strain rate were measured using speckle tracking echocardiography. Results Children with T1DM had increased myocardial contractility both at rest and at all levels of physical stress testing when compared to healthy volunteers. At rest, T1DM patients had significantly higher circumferential strain rate (-2.05 ± 0.35 s -1 ) than healthy controls (-1.86 ± 0.25 s -1 ; p = 0.016). During exercise, diabetic children showed more negative values for longitudinal strain rate (-2.59 ± 0.47 s -1 ) than healthy controls (-2.32 ± 0.41 s -1 ; p = 0.021). Furthermore, in T1DM patients, disease duration inversely correlated with myocardial strain rate and serum HbA1c levels correlated with strain both at rest and during stress testing. Conclusion Long-term impairment of cardiac function in diabetic cardiomyopathy may be preceded by a transient phase of increased myocardial contractility early in the course of T1DM. The extent of hyperglycemia in childhood correlates with the alteration of myocardial contractility.

Abstract 9914: Cardiomyocyte-specific Overexpression of GTP Cyclohydrolase 1 Improves Cardiac Function in Streptozotocin-induced Diabetic Cardiomyopathy

Background: Emerging evidence suggests that GTP cyclohydrolase 1 (GTPCH) is critical for activity of nitric oxide synthase and sarcoplasmic reticulum Ca 2+ ATPase and myocardial relaxation in normal myocardium. We hypothesized that increased expression of GTPCH ameliorates cardiac dysfunction in streptozotocin (STZ)-induced diabetic cardiomyopathy. Methods: Transgenic mice with cardiomyocyte-specific overexpression of human GTPCH gene (GTPCH-Tg) and their wild-type littermates were injected with 50 mg/kg/day STZ (i.p.) for 5 consecutive days to induce diabetes or vehicle as control. Structure and function of the left ventricle were evaluated using echocardiography and in Langendorff-perfused hearts. Western blotting was used to measure expression of GTPCH and p38 mitogen-activated protein kinase (p38 MAPK). Cardiac biopterins were determined by HPLC. Results: Blood glucose concentrations were significantly increased in both GTPCH-Tg and wild-type mice 2 to 12 weeks after STZ injection. There were no significant differences in cardiac structure and function between vehicle-treated GTPCH-Tg and wild-type groups throughout the experiment. Twelve weeks after the injection, STZ-induced diabetes resulted in significant decreases in fractional shortening, the mitral E/A ratio, and ±dP/dt in wild-type mice (fractional shortening: 23±3% vs. 40±3% in vehicle; E/A: 1.36±0.10 vs. 1.87±0.12 in vehicle, n=10, P&lt;0.05) but not GTPCH-Tg mice. The ratio of GTPCH/GAPDH was lower in STZ-treated wild-type than vehicle-treated wild-type mice (0.05±0.01 vs. 0.24±0.05 in vehicle, n=4, P&lt;0.05). In contrast, the ratio of phosphorylated p38 MAPK/total p38 MAPK was significantly higher in STZ-treated wild-type than vehicle-treated wild-type mice. These negative effects of STZ-induced diabetes were abolished by GTPCH overexpression. Cardiac tetrahydrobiopterin levels were dramatically higher in GTPCH-Tg than wild-type mice in both vehicle- and STZ-treated groups. Conclusions: Decreased GTPCH contributes to cardiac dysfunction in STZ-induced diabetic cardiomyopathy. Cardiac overexpression of GTPCH improves cardiac function in diabetic cardiomyopathy by decreasing activation of p38 MAPK and increasing cardiac tetrahydrobioptein levels.

Cardioprotective effect of propranolol on diabetes-induced altered intracellular Ca2+ signaling in rat

We have previously shown that chronic treatment with propranolol had beneficial effects on heart function in rats during increasing-age in a gender-dependent manner. Herein, we hypothesize that propranolol would improve cardiac function in diabetic cardiomyopathy and investigated the benefits of chronic oral administration of propranolol on the parameters of Ca(2+) signaling in the heart of streptozotocin-diabetic rats. Male diabetic rats received propranolol (25 mg/kg, daily) for 12 weeks, 1 week after diabetes induction. Treatment of the diabetic rats with propranolol did not produce a hypoglycaemic effect whereas it attenuated the increased cell size. Basal and β-agonist response levels of left ventricular developed pressure were significantly higher in propranolol-treated diabetic rats relative to untreated diabetics while left ventricular end diastolic pressure of the treated diabetics was comparable to the controls. Propranolol treatment normalized also the prolongation of the action potential in papillary muscles from the diabetic rat hearts. This treatment attenuated the parameters of Ca(2+) transients, depressed Ca(2+) loading of the sarcoplasmic reticulum, and of the basal intracellular Ca(2+) level of diabetic cardiomyocytes. Furthermore, Western blot data indicated that the diabetes-induced alterations in the cardiac ryanodine receptor Ca(2+) release channel's hyperphosphorylation decreased the FKBP12.6 protein level. Also, the high phosphorylated levels of PKA and CaMKII were prevented with propranolol treatment. Chronic treatment with propranolol seems to prevent diabetes-related changes in heart function by controlling intracellular Ca(2+) signaling and preventing the development of left ventricular remodeling in diabetic cardiomyopathy.

Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review.

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.