Mechanisms Of Diabetic Cardiomyopathy Research Articles

Myocardial steatosis, impaired energetics and reduced circumferential strain are early manifestations of diabetic cardiomyopathy and precede structural changes

Background Patients with diabetes mellitus (DM) of longer duration have an increased incidence of heart failure, independent of hypertension and coronary disease, as shown in large population based studies. Mechanisms of diabetic cardiomyopathy are multifactorial and not fully elucidated. Cardiovascular magnetic resonance (CMR) and magnetic resonance spectrocopy (MRS) provide a noninvasive assessment of the functional, structural and metabolic status of the heart. Here we assessed whether subclinical functional, structural and metabolic alterations can be detected using MRI in a patient cohort of early-onset, stable and uncomplicated type 2 DM. Objective The aim of this study was to assess the earliest manifestations of diabetic cardiomyopathy using multiparametric CMR and MRS in a cohort of uncomplicated type 2 DM patients with a short duration of disease. Methods

Investigation of the Protective Effects of Phlorizin on Diabetic Cardiomyopathy indb/dbMice by Quantitative Proteomics

Patients with diabetes often develop hypertension and atherosclerosis leading to cardiovascular disease. However, some diabetic patients develop heart failure without hypertension and coronary artery disease, a process termed diabetic cardiomyopathy. Phlorizin has been reported to be effective as an antioxidant in treating diabetes mellitus, but little is known about its cardioprotective effects on diabetic cardiomyopathy. In this study, we investigated the role of phlorizin in preventing diabetic cardiomyopathy in db/db mice. We found that phlorizin significantly decreased body weight gain and the levels of serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and advanced glycation end products (AGEs). Morphologic observations showed that normal myocardial structure was better preserved after phlorizin treatment. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomics, we identified differentially expressed proteins involved in cardiac lipid metabolism, mitochondrial function, and cardiomyopathy, suggesting that phlorizin may prevent the development of diabetic cardiomyopathy by regulating the expression of key proteins in these processes. We used ingenuity pathway analysis (IPA) to generate an interaction network to map the pathways containing these proteins. Our findings provide important information about the mechanism of diabetic cardiomyopathy and also suggest that phlorizin may be a novel therapeutic approach for the treatment of diabetic cardiomyopathy.

Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima Fatty rats

BackgroundHyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis. Diabetic cardiomyopathy is characterised by cardiac hypertrophy and fibrosis. However, the underlying mechanisms of diabetic cardiomyopathy are not fully understood. This study aimed to investigate the effects of alpha-lipoic acid (ALA) on cardiac energy metabolism, antioxidant effect, and fibrosis in the hearts of Otsuka Long-Evans Tokushima fatty (OLETF) rats.MethodsAnimals were separated into non-diabetic Long-Evans Tokushima Otsuka (LETO) rats and diabetes-prone OLETF rats with or without ALA (200 mg/kg/day) administration for 16 weeks. Diabetic cardiomyopathy was assessed by staining with Sirius Red. The effect of ALA on AMPK signalling, antioxidant enzymes, and fibrosis-related genes in the heart of OLETF rats were performed by Western blot analysis or immunohistochemistry.ResultsWestern blot analysis showed that cardiac adenosine monophosphate-activated kinase (AMPK) signalling was lower in OLETF rats than in LETO rats, and that ALA treatment increased the signalling in OLETF rats. Furthermore, the low antioxidant activity in OLETF rats was increased by ALA treatment. In addition to increased Sirius red staining of collagen deposits, transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) were expressed at higher levels in OLETF rat hearts than in LETO rat hearts, and the levels of these factors were decreased by ALA.ConclusionsALA enhances AMPK signalling, antioxidant, and antifibrogenic effect. Theses findings suggest that ALA may have beneficial effects in the treatment of diabetic cardiomyopathy.

Abstract P250: Reversal of Excessive O -GlcNAcylation Restores Myofilament Function in Diabetic Cardiomyopathy: Potential Role of OGT/OGA Enzymes Localization

Diabetes Mellitus impacts the heart contractile apparatus, as well as cellular ion homeostasis, and energy production systems. Diabetic cardiomyopathy is accompanied by extensive changes in protein post-translational modifications (PTMs), including phosphoylation and O- GlcNAcylation. The cellular and molecular mechanisms of diabetic cardiomyopathy are only partially understood. We previously identified 32 total O- GlcNAcylation sites on MHC, Actin, MLC 1, MLC2, and TnI from normal hearts, and showed that exposure of skinned muscles to GlcNAc induces myofilament Ca 2+ desensitization. In addition, Actin O- GlcNAcylation was increased when exposed to GlcNAc in vitro or to hyperglycemia in two models of Diabetes Mellitus (DM) type 1 and type 2. Our hypothesis is that hyperglycemia directly alters the cycling of O -GlcNAcylation on key myofilament regulatory proteins, and that excessive O -GlcNAcylation is responsible for defective myofilament Ca 2+ -activated response, thus contributing to diabetic cardiomyocyte dysfunction. To test this hypothesis, we have identified OGT localization at the Z-disks where other relevant signaling molecules reside, whereas OGA is localized along the M-band. OGT and OGA affinity for myofilament proteins (Actin, Tm, MLC1 and MLC2) is dramatically up-regulated in the diabetic heart, as assessed by co-immunoprecipitation and Western Blot. We also investigated the effect of O -GlcNAc removal from normal and diabetic skinned muscles by an engineered hexosaminidase (CPJ). We found that 1 hour exposure to CPJ restored myofilament Ca 2+ sensitivity exclusively in diabetic cardiac muscles (EC 50 4.17±0.48 µM pre-CPJ vs 2.73±0.22 µM post-CPJ, n =5 vs n =4, p=0.029 ). These results establish a direct link between cardiac protein hyper- O -GlcNAcylation and diabetic altered cardiac myofilament Ca 2+ sensitivity. Furthermore, OGT and OGA are abundant, and located at strategic signaling compartments, such as the Z-Disk. Overall these data suggest that a specific increase of OGT/OGA affinity towards key myofilament regulatory proteins, and subsequent hyper- O -GlcNAcylation may lead to dysfunctional regulation of myocardial contractility.

Impairment of Right Ventricular Diastolic Function in Early Type 2 Diabetes

Background and Objectives：Diabetes is associated with a unique form of cardiomyopathy in the absence of atherosclerosis. The mechanisms of diabetic cardiomyopathy have not been defined, but is associated with early left ventricular (LV) diastolic dysfunction following an altered LV contractile performance. However, less attention has been paid to the right ventricular (RV) diastolic function in diabetes. Therefore, the changes in the RV ans LV filling dynamics, in patients with early type 2 diabetes, were investigated. Subjects and Methods：The transtricuspid and trans-mitral flows were assessed by transthoracic Doppler echocardiography, at maximal inspiration and expiration, in 48 subjects (mean age：62±9 years, M：F=16：32) with type 2 diabetes (Type 2 DM group) and 34 normal subjects (control group；mean age：59±9 years, M：F=15：19, ranging from 45-75 years of age) with normal LV systolic function and ECG at rest. Subjects with diabetic complication, nephropathy (Cr>1.5 mg/ dL), LVH and COPD were excluded. Results：The mitral E/A ratio and DT (deceleration time) showed no significant difference between the type 2 DM and control groups. The LV and RV systolic functions also showed no significant difference between the two groups. However, the type 2 DM group had a lower tricuspid E/A ratio (0.98±0.25 vs. 1.17±0.21, p<0.001) and a longer tricuspid DT (241±65 msec vs. 208±51 msec, p=0.016) than the control group. Conclusion：The right ventricular diastolic function is frequently abnormal in early type 2 diabetes. This suggests that right ventricular diastolic dysfunction may be an important predictor for the early detection