Dysfunction In Diabetic Cardiomyopathy Research Articles

Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.

Diabetic cardiomyopathy (DCM) is a diabetes mellitus-induced pathophysiological condition characterized by cardiac structural, functional, and metabolic changes that can result in heart failure (HF), in the absence of coronary artery disease, hypertension, and valvular heart disease. Metabolic alterations such as hyperglycemia, insulin resistance, hyperinsulinemia, and increased metabolism of free fatty acids result in oxidative stress, inflammation, advanced glycation end products formation, abnormalities in calcium homeostasis, and apoptosis that are responsible for structural remodeling. Cardiac stiffness, hypertrophy, and fibrosis eventually lead to dysfunction and HF with preserved ejection fraction and/or HF with reduced ejection fraction. In this review, we analyzed in detail the cellular and molecular mechanisms and the metabolic pathways involved in the pathophysiology of DCM. Different phenotypes are observed in DCM, and it is not clear yet if the restrictive and the dilated phenotypes are distinct or represent an evolution of the same disease. Phenotypic differences can be observed between T1DM and T2DM DCM, possibly explained by the different myocardial insulin action. Further studies are needed in order to better understand the underlying mechanisms of DCM and to identify appropriate therapeutic targets and novel strategies to prevent and reverse the progression toward heart failure in diabetic patients.

Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy.

Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart diseases such as valvular or coronary artery dysfunctions. Since the impact of DM on cardiac function is rather silent and slow, early stages of diabetic cardiomyopathy, known as prediabetes, are poorly recognized, and, on many occasions, cardiac illness is diagnosed only after a severe degree of dysfunction was reached. Therefore, exploration and recognition of the initial pathophysiological mechanisms that lead to cardiac dysfunction in diabetic cardiomyopathy are of vital importance for an on-time diagnosis and treatment of the malady. Among the complex and intricate mechanisms involved in diabetic cardiomyopathy, Ca2+ mishandling and mitochondrial dysfunction have been described as pivotal early processes. In the present review, we will focus on these two processes and the molecular pathway that relates these two alterations to the earlier stages and the development of diabetic cardiomyopathy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00424-021-02650-y.

PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance.

Disruption of the mitochondrial quality surveillance (MQS) system contributes to mitochondrial dysfunction in diabetic cardiomyopathy (DCM). In this study, we observed that cardiac expression of phosphoglycerate mutase 5 (PGAM5), a mitochondrial Ser/Thr protein phosphatase, is upregulated in mice with streptozotocin-induced DCM. Notably, DCM-related cardiac structural and functional deficits were negated in cardiomyocyte-specific Pgam5 knockout (Pgam5CKO ) mice. Hyperglycemic stress impaired adenosine triphosphate production, reduced respiratory activity, and prolonged mitochondrial permeability transition pore opening in acutely isolated neonatal cardiomyocytes from control Pgam5f/f mice, and these effects were markedly prevented in cardiomyocytes from Pgam5CKO mice. Likewise, three main MQS-governed processes-namely, mitochondrial fission/fusion cycling, mitophagy, and biogenesis-were disrupted by hyperglycemia in Pgam5f/f , but not in Pgam5CKO , cardiomyocytes. On the basis of bioinformatics prediction of interaction between PGAM5 and prohibitin 2 (PHB2), an inner mitochondrial membrane-associated scaffolding protein, co-immunoprecipitation, and immunoblot assays demonstrated that PGAM5 dephosphorylates PHB2 on Ser91. Transfection of cardiomyocytes with phosphodefective or phosphomimetic Ser91 mutants of PHB2 confirmed a critical role for PGAM5-mediated dephosphorylation of PHB2 in mitochondrial dysfunction associated with hyperglycemic stress. Furthermore, knockin mice expressing phosphomimetic PHB2S91D were resistant to diabetes-induced cardiac dysfunction. Our findings highlight the PGAM-PHB2 axis as a novel and critical regulator of mitochondrial dysfunction in DCM.

Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?

Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O2 and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions.

Effects of Bergamot Polyphenols on Mitochondrial Dysfunction and Sarcoplasmic Reticulum Stress in Diabetic Cardiomyopathy.

Cardiovascular disease is the leading cause of death and disability in the Western world. In order to safeguard the structure and the functionality of the myocardium, it is extremely important to adequately support the cardiomyocytes. Two cellular organelles of cardiomyocytes are essential for cell survival and to ensure proper functioning of the myocardium: mitochondria and the sarcoplasmic reticulum. Mitochondria are responsible for the energy metabolism of the myocardium, and regulate the processes that can lead to cell death. The sarcoplasmic reticulum preserves the physiological concentration of the calcium ion, and triggers processes to protect the structural and functional integrity of the proteins. The alterations of these organelles can damage myocardial functioning. A proper nutritional balance regarding the intake of macronutrients and micronutrients leads to a significant improvement in the symptoms and consequences of heart disease. In particular, the Mediterranean diet, characterized by a high consumption of plant-based foods, small quantities of red meat, and high quantities of olive oil, reduces and improves the pathological condition of patients with heart failure. In addition, nutritional support and nutraceutical supplementation in patients who develop heart failure can contribute to the protection of the failing myocardium. Since polyphenols have numerous beneficial properties, including anti-inflammatory and antioxidant properties, this review gathers what is known about the beneficial effects of polyphenol-rich bergamot fruit on the cardiovascular system. In particular, the role of bergamot polyphenols in mitochondrial and sarcoplasmic dysfunctions in diabetic cardiomyopathy is reported.

Effect of Musk Tongxin Dropping Pill on Myocardial Remodeling and Microcirculation Dysfunction in Diabetic Cardiomyopathy.

Objective To explore the effect of Musk Tongxin Dropping Pill (MTDP) on myocardial remodeling and microcirculation dysfunction in diabetic cardiomyopathy (DCM). Methods Forty male SD rats were randomly divided into control group (control group, n = 10), DCM model group (DCM group, n = 10), DCM model + pioglitazone group (DCM + PLZ group, n = 10), and DCM model + MTDP group (DCM + MTDP group, n = 10). An intraperitoneal single injection of 65 mg/kg streptozotocin (STZ) was used to establish rat model of DCM and the rats in control group were treated with the same dose of sodium citrate buffer solution. DCM + PLZ group was treated with 3 mg/kg/d PLZ by ig after modeling, DCM + MTDP group was treated with 22 mg/kg/d MTDP by ig, and DCM group was treated with 2 ml/kg/d sodium carboxymethyl cellulose (CMC-Na) by ig. The general condition of rats was continuously observed. After intervening for 3 weeks, the random blood glucose of rats was detected by tail vein, and the echocardiography examination was performed. Blood specimens were collected from the abdominal aorta, serum nitric oxide (NO) and endothelin-1 (ET-1) were detected to estimate endothelial function, and tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1β, malondialdehyde (MDA), and superoxide dismutase (SOD) were detected to observe the changes of inflammation and oxidative stress indexes. The heart mass index (HMI) was calculated through the ratio of heart mass (HM) to the corresponding body mass (BM). Myocardial pathological tissue staining was performed. Results Compared with control group, blood glucose in other three groups was higher. Left ventricular end systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) in DCM group showed a significant increase, while left ventricular ejection fraction (LVEF) and heart rate (HR) in this group displayed an obvious decrease (P < 0.01). BM and HM in DCM group exhibited a reduction, and HM/BM × 103 revealed an apparent increase (P < 0.01). The levels of serum NO and SOD were distinctly downregulated (P < 0.01), and the levels of ET-1, MDA, TNF-α, IL-1β, and IL-6 were remarkably upregulated (P < 0.01). Compared with DCM group, a significant decrease was observed in LVSD and LVDD in DCM + MTDP group, while LVEF and HR obviously increased (P < 0.05). BM and HM indicated an apparent increase, but HM/BM ×103 reduced distinctly (P < 0.01). The levels of serum NO and SOD were markedly upregulated (P < 0.05), and the levels of ET-1, MDA, TNF-α, IL-1β, and IL-6 were significantly downregulated (P < 0.05). HE staining showed that myocardial cells arranged neatly in the control group but not in the DCM group. The intercellular space between myocardial cells in DCM group increased, accompanied by damage of myocardial fibers and infiltration of inflammatory cells. Masson staining displayed an increase in interstitial collagen fibers in DCM group. Carstairs staining showed that microembolization occurred in the myocardium in DCM group, while in DCM + MTDP and DCM + PLZ groups the corresponding myocardial pathological changes were significantly improved. Conclusions MTDP might show a positive effect on myocardial remodeling and microcirculation dysfunction in DCM rats.

Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-FoxO1 signalling pathway.

Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 diabetic cardiomyopathy (DCM) have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM. We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. We generated mice overexpressing or lacking Kir6.1 gene specifically in the heart. Kir6.1 overexpression improved cardiac dysfunction in DCM. Cardiac‐specific Kir6.1 knockout aggravated cardiac dysfunction. Kir6.1 regulated the phosphorylation of AKT and Foxo1 in DCM. We further found that Kir6.1 overexpression also improved cardiomyocyte dysfunction and up‐regulated the phosphorylation of AKT and FoxO1 in neonatal rat ventricular cardiomyocytes with insulin resistance. Furthermore, FoxO1 activation down‐regulated the expression of Kir6.1 and decreased the mitochondrial membrane potential (ΔΨm) in cardiomyocytes. FoxO1 inactivation up‐regulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional FoxO1‐binding site. In conclusion, Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT‐FoxO1 signalling pathway.

Reduced reticulum\u2013mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum–mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum–mitochondria interface revealed tighter interactions not compatible with Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R–VDAC interaction and a reduced IP3-stimulated Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum–mitochondria Ca2+ miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.

Abstract 17069: NAD+Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

Diabetes is a risk factor of heart failure and leads to cardiac dysfunction, a condition named diabetic cardiomyopathy (DCM). NAD redox imbalance is observed in diabetic tissues. However, whether NAD redox imbalance promotes cardiac dysfunction in DCM remains unknown. The objective of this study is to determine the causal role of NAD redox imbalance in DCM.Type 1 diabetes was induced in C57BL6 mice by streptozotocin (STZ) injections, and DCM was allowed to develop for 16 weeks. Diabetes-induced chronic stress led to systolic and diastolic cardiac dysfunction along with a lowered NAD/NADH ratio. The diabetogenic protocol was applied to control and cardiac-specific Ndufs4-KO mice (cKO), a mouse model with lowered cardiac NAD/NADH without baseline cardiac dysfunction. Analyses of blood glucose and &gt;200 metabolites in plasma showed no significant change in diabetic control and diabetic cKO mice, suggesting that their hearts experienced similar diabetic stress. Diabetic cKO hearts showed lowered NAD/NADH, aggravated contractile and relaxation dysfunction compared to the diabetic control hearts in both sexes. The data suggest that NAD redox imbalance exacerbated DCM. Collagen staining and transcript analyses of fibrosis-related genes showed no change in diabetic cKO hearts, signifying that the exacerbated dysfunction was due to cardiomyocyte dysfunction. A global protein acetylation was promoted in the diabetic cKO hearts with an increase in SOD2 acetylation levels at lysine-68 (SOD2-K68Ac) and enhanced protein oxidation. Diabetic cKO mice displayed enhanced levels of TnI S150 phosphorylation (TnI-S150Pi), but not phosphorylation of TnI-S23/24 or MyBPc-S282. These data suggest that enhanced oxidative stress and altered myofilament Ca 2+ sensitivity via TnI-S150Pi are responsible for the NAD redox imbalance-exacerbated DCM.To confirm the role of NAD redox imbalance in DCM, we elevated cardiac NAD levels in diabetic cKO mice by cardiac-specific expression of NAMPT. Expression of NAMPT in the heart improved cardiac systolic and diastolic function in diabetic cKO hearts. This was due to increased NAD/NADH ratio and reversed pathogenic mechanisms (lowered SOD2-K68Ac and TnI-S150Pi). This study supports the causal role of NAD redox imbalance in DCM.

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids.

As the powerhouse of the cells, mitochondria play a very important role in ensuring that cells continue to function. Mitochondrial dysfunction is one of the main factors contributing to the development of cardiomyopathy in diabetes mellitus. In early development of diabetic cardiomyopathy (DCM), patients present with myocardial fibrosis, dysfunctional remodeling and diastolic dysfunction, which later develop into systolic dysfunction and eventually heart failure. Cardiac mitochondrial dysfunction has been implicated in the development and progression of DCM. Thus, it is important to develop novel therapeutics in order to prevent the progression of DCM, especially by targeting mitochondrial dysfunction. To date, a number of studies have reported the potential of phenolic acids in exerting the cardioprotective effect by combating mitochondrial dysfunction, implicating its potential to be adopted in DCM therapies. Therefore, the aim of this review is to provide a concise overview of mitochondrial dysfunction in the development of DCM and the potential role of phenolic acids in combating cardiac mitochondrial dysfunction. Such information can be used for future development of phenolic acids as means of treating DCM by alleviating the cardiac mitochondrial dysfunction.

BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes.

Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.

Paradoxical effect of fat diet in matrix metalloproteinases induced mitochondrial dysfunction in diabetic cardiomyopathy.

Diabetic cardiomyopathy represents the main cause of death among diabetic people. Despite this evidence, the molecular mechanisms triggered by impaired glucose and lipid metabolism inducing heart damage remain unclear. The aim of our study was to investigate the effect of altered metabolism on the early stages of cardiac injury in experimental diabetes. For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35 mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot. Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia. Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.

Docosahexaenoic acid protects against palmitate-induced mitochondrial dysfunction in diabetic cardiomyopathy

ObjectiveRegular consumption of n-3 polyunsaturated fatty acids is associated with decreased cardiovascular morbidity and mortality. This study assessed the therapeutic effect of docosahexaenoic acid (DHA) in palmitic acid (PA)-induced cytotoxicity in vitro and in rats fed a high-fat diet (HFD). MethodsH9C2 cells and rat primary cardiomyoblasts were exposed to PA or PA + DHA for 24 h. PA-induced lipotoxicity and mitochondrial dysfunction were evaluated by immunostaining, real-time PCR, cardiomyocyte contraction and transmission electron microscopy. The effects of dietary DHA on diabetic cardiomyopathy were evaluated in male Sprague-Dawley rats fed a reference diet rich in DHA, an HFD, or an HFD with added DHA for 16 weeks. Oxidative stress and lipotoxicity in rat heart tissue were assayed by Masson staining, immunohistochemistry, and TUNEL. ResultsIn vitro studies showed that dietary DHA reduced the occurrence of cardiomyopathy and improved cardiac responses to PA. In the rat model, dietary DHA reduced mitochondrial oxidative stress in HFD-induced diabetic cardiomyopathy. ConclusionDietary DHA reduced mitochondrial oxidative stress and ameliorated PA-induced lipid toxicity. DHA consumption may have had direct effects on cardiovascular risk via myocardial protection.

Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

MiR-410-5p promotes the development of diabetic cardiomyopathy by suppressing PIM1-induced anti-apoptosis

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus that can cause many severe symptoms, such as heart failure, arrhythmia, and sudden death. However, the molecular mechanisms underlying cardiac dysfunction in DCM remain elusive. In this study, we found that miR-410-5p was increased in the myocardial tissue of a diabetes mellitus (DM) rat model. Further studies confirmed that inhibition of miR-410-5p reduced cell apoptosis by regulating the Bcl-2/Bax axis. Through bioinformatics analysis and luciferase reporter assays, we observed that miR-410-5p directly targets PIM1. Moreover, knockdown of miR-410-5p by antagomir-410-5p improved diabetes-induced cardiac function and myocardial tissue structure. In conclusion, our study demonstrated that miR-410-5p might be involved in the progression of DCM by targeting PIM1 and might be a promising therapeutic target for DCM in the future.

PREDICTIVE VALUE OF HEMOGLOBIN A1C FOR SYSTOLIC FUNCTION IN PATIENTS WITH CONGESTIVE HEART FAILURE AND DIABETES MELLITUS: 2D STRAIN STUDY

Mechanisms and determinants of myocardial dysfunction in diabetic cardiomyopathy are poorly understood. Diabetic cardiomyopathy can present in continuum of ejection fraction. We hypothesized that diabetes mellitus is associated with reduced systolic function and myocardial fibrosis even in patients

Exercise modulates heat shock protein 27 activity in diabetic cardiomyopathy

AimsHeat shock protein 27 regulates homeostasis of skeletal and cardiac muscle proteins in various stressful states including diabetes and exercise. Aerobic exercise can inhibit or ameliorate cardiac structural abnormality and dysfunction in diabetic cardiomyopathy. The aim of this study was to evaluate the role of HSP27 in aerobic exercise improving cardiac diastolic dysfunction in type 2 diabetic rats. MethodsForty male Sprague-Dawley rats were randomly divided into the following groups: control, control + aerobic exercise, diabetic, and diabetic + aerobic exercise. Diabetes was induced by feeding with a high-fat high-sugar diet for 7-weeks followed by a single intraperitoneal injection of streptozotocin (30 mg/kg) in male rats. Moderate aerobic exercise training was performed on a treadmill for 8 weeks after induction of diabetes. Key findingsAerobic exercise increased left ventricular end-diastolic internal diameter, left ventricular end-diastolic volume, myocardial HSP27 protein expression, HSP27-S82 phosphorylation levels, pHSP27-titin binding and improved cardiac muscle fibre alignment in diabetic rats. SignificanceOur study indicates that moderate aerobic exercise increases HSP27 activation, improves cardiomyocyte fibre alignment and restores cardiac diastolic function.

Mitochondrial Mechanisms in Diabetic Cardiomyopathy.

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca2+ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.

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

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

The Potential Role of Undercarboxylated Osteocalcin Upregulation in Microvascular Insufficiency in a Rat Model of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology. Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies. Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns. Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.