Onset Of Diabetic Cardiomyopathy Research Articles

The role and therapeutic potential of macrophages in the pathogenesis of diabetic cardiomyopathy.

This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy (DCM). It begins by discussing the origins and diverse subtypes of macrophages, elucidating their spatial distribution and modes of intercellular communication, thereby emphasizing their significance in the pathogenesis of DCM. The review then delves into the intricate relationship between macrophages and the onset of DCM, particularly focusing on the epigenetic regulatory mechanisms employed by macrophages in the context of DCM condition. Additionally, the review discusses various therapeutic strategies aimed at targeting macrophages to manage DCM. It specifically highlights the potential of natural food components in alleviating diabetic microvascular complications and examines the modulatory effects of existing hypoglycemic drugs on macrophage activity. These findings, summarized in this review, not only provide fresh insights into the role of macrophages in diabetic microvascular complications but also offer valuable guidance for future therapeutic research and interventions in this field.

D-pinitol alleviates diabetic cardiomyopathy by inhibiting the optineurin-mediated endoplasmic reticulum stress and glycophagy signaling pathway.

Diabetic cardiomyopathy (DCM) is an important complication resulting in heart failure and death of diabetic patients. However, there is no effective drug for treatments. This study investigated the effect of D-pinitol (DP) on cardiac injury using diabetic mice and glycosylation injury of cardiomyocytes and its molecular mechanisms. We established the streptozotocin-induced SAMR1 and SAMP8 mice and DP (150 mg/kg/day) intragastrically and advanced glycation end-products (AGEs)-induced H9C2 cells. H9C2 cells were transfected with optineurin (OPTN) siRNA and overexpression plasmids. The metabolic disorder indices, cardiac dysfunction, histopathology, immunofluorescence, western blot, and immunoprecipitation were investigated. Our results showed that DP reduced the blood glucose and AGEs, and increased the expression of heart OPTN in diabetic mice and H9C2 cells, thereby inhibiting the endoplasmic reticulum stress (GRP78, CHOP) and glycophagy (STBD1, GABARAPL1), and alleviating the myocardial apoptosis and fibrosis of DCM. The expression of filamin A as an interaction protein of OPTN downregulated by AGEs decreased OPTN abundance. Moreover, OPTN siRNA increased the expression of GRP78, CHOP, STBD1, and GABARAPL1 and inhibited the expression of GAA via GSK3β phosphorylation and FoxO1. DP may be helpful to treat the onset of DCM. Targeting OPTN with DP could be translated into clinical application in the fighting against DCM.

Identification of hub genes and potential ceRNA networks of diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM), a common complication of diabetes, is defined as ventricular dysfunction in the absence of underlying heart disease. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), play a crucial role in the development of DCM. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify key modules in DCM-related pathways. DCM-related miRNA-mRNA network and DCM-related ceRNA network were constructed by miRNA-seq to identify hub genes in these modules. We identified five hub genes that are associated with the onset of DCM, including Troponin C1 (Tnnc1), Phospholamban (Pln), Fatty acid binding proteins 3 (Fabp3), Popeye domain containing 2 (Popdc2), and Tripartite Motif-containing Protein 63 (Trim63). miRNAs that target the hub genes were mainly involved in TGF-β and Wnt signaling pathways. GO BP enrichment analysis found these miRNAs were involved in the signaling of TGF-β and glucose homeostasis. Q-PCR results found the gene expressions of Pln, Fabp3, Trim63, Tnnc1, and Popdc2 were significantly increased in DCM. Our study identified five hub genes (Tnnc1, Pln, Fabp3, Popdc2, Trim63) whose associated ceRNA networks are responsible for the onset of DCM.

Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice

Background: Mesenchymal stromal cells (MSCs) are an attractive cell type for cell therapy given their immunomodulatory, anti-fibrotic, and endothelial-protective features. The heparin sulfate proteoglycan, syndecan-2/CD362, has been identified as a functional marker for MSC isolation, allowing one to obtain a homogeneous cell product that meets regulatory requirements for clinical use. We previously assessed the impact of wild-type (WT), CD362−, and CD362+ MSCs on local changes in protein distribution in left ventricular (LV) tissue and on LV function in an experimental model of early-onset diabetic cardiomyopathy. The present study aimed to further explore their impact on mechanisms underlying diastolic dysfunction in this model.Materials: For this purpose, 1 × 106 WT, CD362−, or CD362+ MSCs were intravenously (i.v.) injected into 20-week-old diabetic BKS.Cg-m+/+Leprdb/BomTac, i.e., db/db mice. Control animals (db+/db) were injected with the equivalent volume of phosphate-buffered saline (PBS) alone. After 4 weeks, mice were sacrificed for further analysis.Results: Treatment with all three MSC populations had no impact on blood glucose levels in db/db mice. WT, CD362−, and CD362+ MSC application restored LV nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) levels in db/db mice, which correlated with a reduction in cardiomyocyte stiffness. Furthermore, all stromal cells were able to increase arteriole density in db/db mice. The effect of CD362+ MSCs on NO and cGMP levels, cardiomyocyte stiffness, and arteriole density was less pronounced than in mice treated with WT or CD362− MSCs. Analysis of collagen I and III protein expression revealed that fibrosis had not yet developed at this stage of experimental diabetic cardiomyopathy. All MSCs reduced the number of cardiac CD3+ and CD68+ cells in db/db mice, whereas only splenocytes from CD362−- and CD362+-db/db mice exhibited a lower pro-fibrotic potential compared to splenocytes from db/db mice.Conclusion: CD362+ MSC application decreased cardiomyocyte stiffness, increased myocardial NO and cGMP levels, and increased arteriole density, although to a lesser extent than WT and CD362− MSCs in an experimental model of early-onset diabetic cardiomyopathy without cardiac fibrosis. These findings suggest that the degree in improvement of cardiomyocyte stiffness following CD362+ MSC application was insufficient to improve diastolic function.

Effects of D-pinitol on myocardial apoptosis and fibrosis in streptozocin-induced aging-accelerated mice.

Diabetic cardiomyopathy (DCM) causes heart failure and increases the mortality in diabetic patients. Myocardial apoptosis and fibrosis are the main features of DCM and aging. The aim is to study the underlying mechanism of D-pinitol (DP) on myocardial apoptosis and fibrosis in an elderly diabetic mouse model. The diabetic model was established by SAMP-8 mice that were injected with streptozotocin daily for five consecutive days. The mice were administrated of DP (150mgkg-1 day-1 ) by gavage for 10weeks. The common metabolic disorder indices, cardiac dysfunction, oxidative stress, myocardial apoptosis and fibrosis, and PI3K/Akt/mTOR pathway were investigated. Our findings suggested that DP has a protective effect on DCM, which may be related to regulating oxidative stress, and PI3K/Akt/mTOR pathway involving cardiac fibrosis and apoptosis. DP may be a novel clinical application in fighting against DCM. PRACTICAL APPLICATIONS: D-pinitol (DP) was found in large quantities in soybean and legume foods. DP has a variety of functions, including hypoglycemic, anti-oxidation, anti-inflammatory, cardioprotective, and anti-tumor activity. We used the streptozotocin-induced SAMP8 mice as the diabetic model and treated with DP. We found that DP can improve cardiac dysfunction and inhibits the oxidative stress, myocardial apoptosis and fibrosis. DP has a significant effect on diabetic cardiomyopathy (DCM). The molecular mechanisms are related to regulating oxidative stress, and PI3K/Akt/mTOR pathway involving cardiac fibrosis and apoptosis. DP can prevent and/or delay the onset of DCM.

Pathogenesis of Diabetic Cardiomyopathy and Role of miRNA.

Diabetic cardiomyopathy is characterized as abnormal function and structure of myocardium associated with diabetes irrespective of other cardiac risk factors like hypertension or coronary artery disease (CAD). The pathogenesis of DCM was not well understood in the past due to its complexity but it has been discovered recently. Various factors are found to be associated with the onset of DCM including impaired calcium handling, remodeling of extracellular matrix (ECM), increased oxidative stress, altered metabolism, mitochondrial dysfunction, and endothelial dysfunction. Micro-RNAs (miRNAs) are also found to be of great importance in the pathogenesis of DCM. Different miRNAs like miR-126, miR-24, miR-1, miR-155, miR-499, and miR-199a are found to be associated with different types of heart diseases like CAD and myocardial infarction. Studies have shown that the miRNA plays a crucial role in the development of DCM and it was found that the expression levels of different miRNAs differ in patients as compared to healthy individuals. This review focuses on the pathogenesis of DCM and various factors involved in the onset of diabetic car-diomyopathy. Moreover, the probable role of miRNA in the pathogenesis of DCM is also discussed.

Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats.

Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX™ staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a “frail” myocardial tissue unable to adapt itself to stress.

Identification of potential biomarkers for predicting the early onset of diabetic cardiomyopathy in a mouse model

Type 2 diabetes (T2D) is characterized by metabolic derangements that cause a shift in substrate preference, inducing cardiac interstitial fibrosis. Interstitial fibrosis plays a key role in aggravating left ventricular diastolic dysfunction (LVDD), which has previously been associated with the asymptomatic onset of heart failure. The latter is responsible for 80% of deaths among diabetic patients and has been termed diabetic cardiomyopathy (DCM). Through in silico prediction and subsequent detection in a leptin receptor-deficient db/db mice model (db/db), we confirmed the presence of previously identified potential biomarkers to detect the early onset of DCM. Differential expression of Lysyl Oxidase Like 2 (LOXL2) and Electron Transfer Flavoprotein Beta Subunit (ETFβ), in both serum and heart tissue of 6–16-week-old db/db mice, correlated with a reduced left-ventricular diastolic dysfunction as assessed by high-resolution Doppler echocardiography. Principal component analysis of the combined biomarkers, LOXL2 and ETFβ, further displayed a significant difference between wild type and db/db mice from as early as 9 weeks of age. Knockdown in H9c2 cells, utilising siRNA of either LOXL2 or ETFβ, revealed a decrease in the expression of Collagen Type I Alpha1 (COL1A1), a marker known to contribute to enhanced myocardial fibrosis. Additionally, receiver-operating curve (ROC) analysis of the proposed diagnostic profile showed that the combination of LOXL2 and ETFβ resulted in an area under the curve (AUC) of 0.813, with a cut-off point of 0.824, thus suggesting the favorable positive predictive power of the model and further supporting the use of LOXL2 and ETFβ as possible early predictive DCM biomarkers.

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.

Abnormalities of the cardiac stem and progenitor cell compartment in experimental and human diabetes

Diabetic cardiomyopathy consists of a series of structural and functional changes. Accumulating evidence supports the concept that a “cardiac stem cell compartment disease” plays an important role in the pathophysiology of diabetic cardiomyopathy. In diabetic hearts, human cardiac stem/progenitor cells (CSPC) are reduced and manifest defective proliferative capacity. Hyperglycaemia, hyperlipidemia, inflammation, and the consequent oxidative stress are enhanced in diabetes: these conditions can induce defects in both growth and survival of these cells with an imbalance between cell death and cell replacement, thus favouring the onset of diabetic cardiomyopathy and its progression towards heart failure. The preservation of CSPC compartment can contribute to counteract the negative impact of diabetes on the myocardium. The recent studies summarized in this review have improved our understanding of the development and stem cell biology within the cardiovascular system. However, several issues remain unsolved before cell therapy can become a clinical therapeutically relevant strategy.

Epicardial left ventricular myocardial rotation correlates with resting myocardial blood flow in type 2 diabetes mellitus patients with angiographically normal coronary arteries

Background Type 2 Diabetes Mellitus (T2DM) and prediabetes are associated with an increased cardiovascular risk and heart failure independent of the presence of obstructive coronary artery disease, caused in part by myocardial microvascular dysfunction. Recent studies have reported contractile dysfunction and increased rotation with the onset of diabetic cardiomyopathy in uncomplicated T2DM patients. Independently, higher resting myocardial blood flow (MBF) has been reported in T2DM. The objective of this study was to determine whether there is a correlation between LV Epicardial Rotation (LV ER) and resting MBF in T2DM patients with angiographically normal coronaries, measured by tissue tagging and perfusion cardiovascular Magnetic Resonance (CMR). Methods Sixty five patients with no coronary stenosis >30% on invasive angiography were recruited and categorized into T2DM, prediabetes and normal controls groups according to American Diabetes Association guidelines. All patients underwent rest and adenosine stress myocardial perfusion CMR at a single mid-LV location, cine imaging covering the entire heart and myocardial tissue tagging in three LV short axis locations (apical, mid LV and basal). LV volumes and mass were calculated from cine images. LV rotation in three myocardial layers (endocardial, midmyocardial and epicardial) was calculated from CSPAMM tissue images using Tag Track (Gyrotools, Zurich). For this study, only rest MBF was calculated using Fermi-constrained deconvolution for the entire myocardium. Results Patient characteristics and results are shown in Table 1. Patients with T2DM had significantly higher resting MBF than the two other groups. Corresponding mid LV ER was higher in T2DM patients compared to patients with prediabetes and normal controls (Figure 1) (not statistically significant). Univariate analysis showed a significant positive correlation between MBF and LV ER in the entire study population (Pearson coefficient (r) of 0.25, p = 0.05). In the individual groups, the linear determination coefficient (R2) showed that LV ER in T2DM patients had stronger positive correlation (R2 = 0.31) with resting MBF than in patients with prediabetes (R2 = 0.16) and controls (R2 = 0.29), Figure 1. Conclusions T2DM patients when compared to age-matched patients with prediabetes and normal controls have higher peak LV ER. Resting MBF correlates with LV ER. These results suggest that LV ER analysis in uncomplicated T2DM patients may be useful for non-invasive screening of early subtle contractile dysfunction associated with microvascular dysfunction in diabetes patients.

Catalase alleviates cardiomyocyte dysfunction in diabetes: role of Akt, Forkhead transcriptional factor and silent information regulator 2

Oxidative stress has been speculated to play an essential role in diabetic cardiomyopathy. This study was designed to examine the effect of the antioxidant catalase on diabetes-induced cardiomyocyte dysfunction and the cellular mechanisms involved. Adult wild-type (FVB) and transgenic mice with cardiac-specific overexpression of catalase were made diabetic by a single injection of streptozotocin (STZ, 220 mg/kg; i.p., maintained for two weeks). Cardiomyocyte contractile properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR 90), maximal velocity of shortening/relengthening (± dL/dt), intracellular Ca 2+ level and decay rate. STZ depressed − dL/dt, prolonged TPS and TR 90, elevated resting intracellular Ca 2+ level and reduced intracellular Ca 2+ decay in FVB myocytes. While catalase exhibited little effect on contractile and intracellular Ca 2+ properties in control myocytes, it negated diabetes-induced cardiomyocyte mechanical abnormalities. Diabetic myocytes exhibited enhanced levels of reactive oxygen species and apoptosis, which were alleviated by catalase. Western blot analysis revealed that diabetes reduced Akt phosphorylation, enhanced the silent information regulator 2 (Sirt2), and upregulated Forkhead transcriptional factor Foxo3a as well as glycogen synthase kinase-3β (GSK-3β) and pGSK-3β. While catalase itself exhibited little effect on these proteins or their phosphorylation (with the exception of Sirt2), it significantly attenuated diabetes-induced alteration in pAkt, Foxo3a and Sirt2 without affecting GSK-3β. Inhibition of Sirt2 using splitomicin impaired cardiomyocyte contractile function (reduced PS, ± dL/dt, prolonged TPS and TR 90). In summary, our data suggest potential roles of Akt, Foxo3a and Sirt2 in the onset of diabetic cardiomyopathy and the therapeutic potential of catalase.