Dysfunction In Diabetic Cardiomyopathy Research Articles

Ginsenoside Rb1 reduces oxidative/carbonyl stress damage and dysfunction of RyR2 in the heart of streptozotocin-induced diabetic rats

BackgroundOxidative stress may contribute to cardiac ryanodine receptor (RyR2) dysfunction in diabetic cardiomyopathy. Ginsenoside Rb1 (Rb1) is a major pharmacologically active component of ginseng to treat cardiovascular diseases. Whether Rb1 treat diabetes injured heart remains unknown. This study was to investigate the effect of Rb1 on diabetes injured cardiac muscle tissue and to further investigate its possible molecular pharmacology mechanisms.MethodsMale Sprague-Dawley rats were injected streptozotocin solution for 2 weeks, followed 6 weeks Rb1 or insulin treatment. The activity of SOD, CAT, Gpx, and the levels of MDA was measured; histological and ultrastructure analyses, RyR2 activity and phosphorylated RyR2(Ser2808) protein expression analyses; and Tunel assay were performed.ResultsThere was decreased activity of SOD, CAT, Gpx and increased levels of MDA in the diabetic group from control. Rb1 treatment increased activity of SOD, CAT, Gpx and decreased the levels of MDA as compared with diabetic rats. Neutralizing the RyR2 activity significantly decreased in diabetes from control, and increased in Rb1 treatment group from diabetic group. The expression of phosphorylation of RyR2 Ser2808 was increased in diabetic rats from control, and were attenuated with insulin and Rb1 treatment. Diabetes increased the apoptosis rate, and Rb1 treatment decreased the apoptosis rate. Rb1 and insulin ameliorated myocardial injury in diabetic rats.ConclusionsThese data indicate that Rb1 could be useful for mitigating oxidative damage, reduced phosphorylation of RyR2 Ser2808 and decreased the apoptosis rate of cardiomyocytes in diabetic cardiomyopathy.

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

Abstract 1824 SARM1 NAD hydrolase deficiency ameliorates cardiac and mitochondrial dysfunction in diabetic cardiomyopathy through regulation of mitophagy

Abstract 1824 SARM1 NAD hydrolase deficiency ameliorates cardiac and mitochondrial dysfunction in diabetic cardiomyopathy through regulation of mitophagy

Role of AMP deaminase in diabetic cardiomyopathy.

Diabetes mellitus is one of the major causes of ischemic and nonischemic heart failure. While hypertension and coronary artery disease are frequent comorbidities in patients with diabetes, cardiac contractile dysfunction and remodeling occur in diabetic patients even without comorbidities, which is referred to as diabetic cardiomyopathy. Investigations in recent decades have demonstrated that the production of reactive oxygen species (ROS), impaired handling of intracellular Ca2+, and alterations in energy metabolism are involved in the development of diabetic cardiomyopathy. AMP deaminase (AMPD) directly regulates adenine nucleotide metabolism and energy transfer by adenylate kinase and indirectly modulates xanthine oxidoreductase-mediated pathways and AMP-activated protein kinase-mediated signaling. Upregulation of AMPD in diabetic hearts was first reported more than 30years ago, and subsequent studies showed similar upregulation in the liver and skeletal muscle. Evidence for the roles of AMPD in diabetes-induced fatty liver, sarcopenia, and heart failure has been accumulating. A series of our recent studies showed that AMPD localizes in the mitochondria-associated endoplasmic reticulum membrane as well as the sarcoplasmic reticulum and cytosol and participates in the regulation of mitochondrial Ca2+ and suggested that upregulated AMPD contributes to contractile dysfunction in diabetic cardiomyopathy via increased generation of ROS, adenine nucleotide depletion, and impaired mitochondrial respiration. The detrimental effects of AMPD were manifested at times of increased cardiac workload by pressure loading. In this review, we briefly summarize the expression and functions of AMPD in the heart and discuss the roles of AMPD in diabetic cardiomyopathy, mainly focusing on contractile dysfunction caused by this disorder.

Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of Its Pathology.

Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases the risk of a specific form of cardiomyopathy referred to as diabetic cardiomyopathy (DbCM), originally defined as ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. Herein, we provide an overview on the key mediators of DbCM, with an emphasis on the role for perturbations in cardiac substrate metabolism. We discuss key mechanisms regulating metabolic dysfunction in DbCM, with additional focus on the role of metabolites as signalling molecules within the diabetic heart. Furthermore, we discuss the preclinical approaches to target these perturbations to alleviate DbCM. With several advancements in our understanding, we propose "diastolic dysfunction in the presence of altered myocardial metabolism in a person with diabetes, but absence of other known causes of cardiomyopathy and/or hypertension", as a new definition for, or approach to classify, DbCM. However, we recognize that no definition can fully explain the complexity of why some individuals with DbCM exhibit diastolic dysfunction, whereas others develop systolic dysfunction. Due to DbCM sharing pathological features with heart failure with preserved ejection fraction (HFpEF), the latter of which is more prevalent in the diabetic population, it is imperative to determine whether effective management of DbCM decreases HFpEF prevalence.

Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.

Empagliflozin improves mitochondrial dysfunction in diabetic cardiomyopathy by modulating ketone body metabolism and oxidative stress

Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it may be an important area of research and development as a therapeutic target for DCM. Cumulative cardiovascular trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in diabetic populations. Whether SGLT2 inhibitors improve DCM by enhancing ketone body metabolism remains and whether they help prevent oxidative damage remains to be clarified. Here, we present the combined results of nine GSE datasets for diabetic cardiomyopathy (GSE215979, GSE161931, GSE145294, GSE161052, GSE173384, GSE123975, GSE161827, GSE210612, and GSE5606). We found significant up-regulated gene 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) and down-regulated gene 3-hydroxybutyrate dehydrogenase (BDH1) and 3-oxoacid CoA-transferase1 (OXCT1), respectively. Based on the analysis of the constructed protein interaction network, it was found that HMGCS2 was in the core position of the interaction network. In addition, Gene ontology (GO) enrichment analysis mainly focused on redox process, acyl-CoA metabolic process, catalytic activity, redox enzyme activity and mitochondria. The activity of HMGCS2 in DCM heart was increased, while the expression of ketolysis enzymes BDH1 and OXCT1 was inhibited. In vivo, Empagliflozin (Emp) treated DCM group significantly decreased ventricular weight, myocardial cell cross-sectional area, and myocardial fibrosis. In addition, Emp further promoted the activity of BDH1 and OXCT1, increased the utilization of ketone bodies, further promoted the activity of HMGCS2 in DCM, and increased the synthesis of ketone bodies, prevented mitochondrial breakage and dysfunction, increased myocardial ATP to provide sufficient energy, inhibited oxidative stress and apoptosis of cardiac cells ex vivo, and improved the myocardial dysfunction of DCM. Emp can improve mitochondrial dysfunction in diabetic cardiomyopathy by regulating ketone body metabolism and oxidative stress. These findings provide a theoretical basis for evaluating Emp as a treatment for DCM.

Effects of non-coding RNAs and RNA-binding proteins on mitochondrial dysfunction in diabetic cardiomyopathy.

Vascular complications are the main cause of diabetes mellitus-associated morbidity and mortality. Oxidative stress and metabolic dysfunction underly injury to the vascular endothelium and myocardium, resulting in diabetic angiopathy and cardiomyopathy. Mitochondrial dysfunction has been shown to play an important role in cardiomyopathic disruptions of key cellular functions, including energy metabolism and oxidative balance. Both non-coding RNAs and RNA-binding proteins are implicated in diabetic cardiomyopathy, however, their impact on mitochondrial dysfunction in the context of this disease is largely unknown. Elucidating the effects of non-coding RNAs and RNA-binding proteins on mitochondrial pathways in diabetic cardiomyopathy would allow further insights into the pathophysiological mechanisms underlying diabetic vascular complications and could facilitate the development of new therapeutic strategies. Stem cell-based models can facilitate the study of non-coding RNAs and RNA-binding proteins and their unique characteristics make them a promising tool to improve our understanding of mitochondrial dysfunction and vascular complications in diabetes.

L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways.

To explore the beneficial effects of L-carnitine on cardiac microvascular dysfunction in diabetic cardiomyopathy from the perspectives of mitophagy and mitochondrial integrity. Male db/db and db/m mice were randomly assigned to groups and were treated with L-carnitine or a solvent for 24 weeks. Endothelium-specific PARL overexpression was attained via adeno-associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild-type CPT1a, mutant CPT1a, or PARL were transfected into endothelial cells exposed to high glucose and free fatty acid (HG/FFA) injury. Cardiac microvascular function, mitophagy, and mitochondrial function were analyzed by immunofluorescence and transmission electron microscopy. Protein expression and interactions were assessed by western blotting and immunoprecipitation. L-carnitine treatment enhanced microvascular perfusion, reinforced endothelial barrier function, repressed the endothelial inflammatory response, and maintained the microvascular structure in db/db mice. Further results demonstrated that PINK1-Parkin-dependent mitophagy was suppressed in endothelial cells suffering from diabetic injury, and these effects were largely alleviated by L-carnitine through the inhibition of PARL detachment from PHB2. Moreover, CPT1a modulated the PHB2-PARL interaction by directly binding to PHB2. The increase in CPT1a activity induced by L-carnitine or amino acid mutation (M593S) enhanced the PHB2-PARL interaction, thereby improving mitophagy and mitochondrial function. In contrast, PARL overexpression inhibited mitophagy and abolished all the beneficial effects of L-carnitine on mitochondrial integrity and cardiac microvascular function. L-carnitine treatment enhanced PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1a, thereby reversing mitochondrial dysfunction and cardiac microvascular injury in diabetic cardiomyopathy.

Lysosomal dysfunction in diabetic cardiomyopathy.

Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.

Subcellular Recycling of CD36 as Target to Rescue Lipid Overload‐induced Myocardial Contractile Dysfunction

BackgroundDisturbances in cardiac metabolism are increasingly being recognized as crucial drivers of the development and progression of heart disease and ageing. In particular, lipid overload due to Western life style or obesity eventually elicits cardiac insulin resistance and contractile dysfunction (referred to as diabetic cardiomyopathy). As a result, there is an urgent unmet clinical need for treatments that can directly target metabolic defects in heart failure. The transmembrane protein CD36 both facilitates myocardial fatty acid uptake and regulates this process by its subcellular recycling between endosomes and the sarcolemma. In turn, CD36 recycling was recently found to be regulated by instantaneous changes in activity of vacuolar‐type H+‐ATPase (v‐ATPase) in the endosomes, as controlled by rapid assembly and disassembly of V0 and V1 subunits of v‐ATPase.HypothesisRegulation of subcellular recycling of CD36 by v‐ATPase is an effective target for metabolic modulation therapy in diabetic cardiomyopathy.ObjectiveTo investigate whether manipulating v‐ATPase activity, and thereby CD36 recycling, rescues insulin resistance and contractile dysfunction of the diabetic heart.MethodsIsolated rat cardiomyocytes and human (iPSC‐derived and differentiated) cardiomyocytes were treated with bafilomycin (v‐ATPase inhibitor) or energy substrates, i.e., fatty acids, glucose, amino acids (AAs) or b‐hydroxy butyrate (HB). In addition, rats in vivo were treated with AAs. v‐ATPase activity (assembly status), substrate transporter localization (CD36 and glucose transporter GLUT4) and fatty acid and glucose uptake rates (in absence or presence of insulin) were measured.ResultsIn rat and human cardiomyocytes both bafilomycin, excess palmitate and HB inhibited v‐ATPase activity, increased sarcolemmal CD36 content, increased fatty acid uptake and lipid accumulation, and elicited contractile dysfunction. However, the latter could be rescued by excess glucose or AAs, concomitant with in each case a similar increase of v‐ATPase activity and CD36 reinternalization, while glucose uptake was increased. Hence, v‐ATPase activity/assembly is required for retention of CD36 in endosomes. In case of AAs, v‐ATPase (re)assembly was dependent on mTORC1 activation. In high fat diet‐fed rats, AAs had a similar beneficial action at the myocellular level.ConclusionsThese novel data suggest a pivotal role for endosomal v‐ATPase activity and subcellular CD36 recycling in determining myocardial substrate preference, in particular fatty acids versus glucose. The molecular mechanism involves assembly/disassembly of the V0 and V1 subunits of v‐ATPase, allowing a rapid change in activity. Lipid accumulation and contractile dysfunction in diabetic cardiomyopathy is aggravated by HB but resolved by AAs.PerspectiveSpecific amino acids acting through v‐ATPase reassembly may be an effective nutraceutical therapy in diabetic cardiomyopathy, but ketone bodies should not be used as these may aggravate lipid accumulation and contractile dysfunction.

The Regulatory Role of miR‐21 in Coronary Microcirculation

IntroductionCoronary microvascular dysfunction is characterized by impaired endothelial‐dependent vasodilation. These impairments are seen in diabetic cardiomyopathy (DCM), coronary artery disease (CAD) and ischemia with non‐obstructive coronary artery (INOCA), Takotsubo cardiomyopathy, myocardial infarction with non‐obstructive coronary artery disease (MINOCA), and heart failure with preserved ejection fraction (HFpEF), but detailed mechanisms have yet to be elucidated.MethodsmicroRNA‐21 (miR‐21) global and conditional knockout mice were used to study how miR‐21 regulates coronary microcirculation in pathological conditions like DCM. Both genetic (db/db) and diet‐induced diabetic models were used. Coronary arteries were isolated, and endothelial‐dependent vasodilation was assessed using myography (DMT). In vivo myocardial blood flow (MBF) under stress was measured by contrast echocardiography or doppler after the treatment with different dosages of norepinephrine. Quantitative polymerase chain reaction (qPCR) was performed for gene expression analysis. Trichrome staining and histology were performed for structural changes of the hearts.ResultsOur preliminary data show that miR‐21 is upregulated in DCM and the deficiency of miR‐21 restores the endothelial‐dependent vasodilation in isolated diabetic coronary arterioles and coronary blood flow under stress in DCM through the mechanism that miR‐21 prevents the mediator of coronary vasodilation switching from NO to H2O2 in diabetes.ConclusionsmiR‐21 regulates microvascular dysfunction in DCM. Further genetic profiling will elucidate the pathways and mechanisms converging with miR‐21 to regulate microvascular function.

The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is described as abnormalities of myocardial structure and function in diabetic patients without other well-established cardiovascular factors. Although multiple pathological mechanisms involving in this unique myocardial disorder, mitochondrial dysfunction may play an important role in its development of DCM. Recently, considerable progresses have suggested that mitochondrial biogenesis is a tightly controlled process initiating mitochondrial generation and maintaining mitochondrial function, appears to be associated with DCM. Nonetheless, an outlook on the mechanisms and clinical relevance of dysfunction in mitochondrial biogenesis among patients with DCM is not completely understood. In this review, hence, we will summarize the role of mitochondrial biogenesis dysfunction in the development of DCM, especially the molecular underlying mechanism concerning the signaling pathways beyond the stimulation and inhibition of mitochondrial biogenesis. Additionally, the evaluations and potential therapeutic strategies regarding mitochondrial biogenesis dysfunction in DCM is also presented.

Soluble Epoxide Hydrolase Inhibition Protected against Diabetic Cardiomyopathy through Inducing Autophagy and Reducing Apoptosis Relying on Nrf2 Upregulation and Transcription Activation.

Background Many patients with diabetes die from diabetic cardiomyopathy (DCM); however, effective strategies for the prevention or treatment of DCM have not yet been clarified. Methods Leptin receptor-deficient (db/db) mice were treated with either the soluble epoxide hydrolase (sEH) inhibitor AUDA or vehicle alone. A virus carrying Nrf2 shRNA was used to manipulate Nrf2 expression in db/db mice. Cardiac structures and functions were analyzed using echocardiography and hemodynamic examinations. Primary cardiomyocytes cultured under high glucose and high fat (HGHF) conditions were used to conduct in vitro loss-of-function assays after culture in the presence or absence of AUDA (1 μM). Fluorescence microscopy-based detection of mCherry-GFP-LC3 was performed to assess autophagic flux. Results The sEH inhibitor AUDA significantly attenuated ventricular remodeling and ameliorated cardiac dysfunction in db/db mice. Interestingly, AUDA upregulated Nrf2 expression and promoted its nuclear translocation in db/db mice and the HGHF-treated cardiomyocytes. Additionally, AUDA increased autophagy and decreased apoptosis in db/db mice heart. Furthermore, the administration of AUDA promoted autophagic flux and elevated LC3-II protein level in the presence of bafilomycin A1. However, AUDA-induced autophagy was abolished, and the antiapoptotic effect was partially inhibited upon Nrf2 knockdown. Conclusion Our findings suggest that the sEH inhibitor AUDA attenuates cardiac remodeling and dysfunction in DCM via increasing autophagy and reducing apoptosis, which is relevant to activate Nrf2 signaling pathway.

Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats.

Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.

Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile Associated With Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, leading to heart failure and increased risk for death in diabetic patients. To investigate the molecular mechanisms involved in DbCM, we performed a quantitative proteomic profiling analysis in the left ventricle (LV) of type 2 diabetic mice. Six-month-old C57BL/6J-lepr/lepr (db/db) mice exhibited DbCM associated with diastolic dysfunction and cardiac hypertrophy. Using quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in the LVs of db/db mice, majorly associated with the regulation of energy metabolism. The subunits of ATP synthase that form the F1 domain, and Cytochrome c1, a catalytic core subunit of the complex III primarily responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by diabetic heart, resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1β subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, the atypical kinase COQ8A, an essential lipid-soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from diabetic mice to augment mitochondrial ATP energetics, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production. Preserved basal mitochondrial respiration along with the markedly reduced maximal respiratory capacity in the LVs of db/db mice corroborate the association between altered mitochondrial metabolic profile and cardiac dysfunction in DbCM.

Irisin alleviates high glucose-induced hypertrophy in H9c2 cardiomyoblasts by inhibiting endoplasmic reticulum stress

BackgroundEndoplasmic reticulum stress (ERS) plays an important role in the process of myocardial hypertrophy in diabetic cardiomyopathy (DCM). Irisin, a novel cytokine, has been found to protect against cardiac diastolic dysfunction in DCM. We aimed to investigate the role of irisin in cardiac hypertrophy and to elucidate the underlying mechanisms. MethodsH9c2 cells were induced with 33 mM glucose to construct a cardiac hypertrophy cell model, which was then treated with irisin in the presence or absence of the ERS inducer tunicamycin (TM). The cell surface area was measured by FITC-phalloidin staining. The atrial natriuretic peptide levels were detected by an enzyme-linked immunosorbent assay. Furthermore, the expression of the ERS-related proteins, P-PERK, PERK, IRE1α and GRP78, was detected by western blotting. ResultsIrisin significantly reduced myocardial hypertrophy and suppressed high glucose (HG)-induced oxidative stress. Meanwhile, the protective effect of irisin on cardiomyoblasts was reversed by the ERS inducer, TM. Additionally, we detected ERS-associated signaling pathway proteins and found that irisin significantly reduced the protein expression levels of GRP78 and p-PERK/PERK. ConclusionThese results suggest that irisin ameliorates HG-induced cardiac hypertrophy by inhibiting ERS.

Spermine Regulates Immune and Signal Transduction Dysfunction in Diabetic Cardiomyopathy.

BackgroundDiabetic cardiomyopathy (DCM) is a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Exploring the transcriptomics of DCM is of great significance for understanding the biology of the disease and for guiding new therapeutic targets for the potential therapeutic effect of spermine (SPM).Methods and ResultsBy using a mouse DCM model, we analyzed the transcriptome of the myocardium, before/after treatment with SPM. Using RNA sequencing (RNA-seq), we identified 1,318 differentially expressed genes (DEGs), with 636 being upregulated and 682 being downregulated in DCM compared to control check (CK). We then identified 1,393 DEGs, with 887 being upregulated and 506 being downregulated in SPM compared to DCM. Kyoto Encyclopedia of Genes And Genomes (KEGG) analysis demonstrated that the DEGs were significantly enriched in the immune system and signal transduction-related pathways. UpSet Venn analysis showed that 174 DEGs in DCM could be reversed by SPM, with 45 candidates related to immune system and related signal transduction pathways. Trend analysis demonstrated the dynamic changes in gene levels in DCM and SPM treatment, shown as 49 immune and signal transduction-related candidates were significantly enriched in some classical pathways, such as complement and coagulation cascades and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway. To further reveal the protective mechanism of SPM to DCM, we predicted 14 overlapped transcription factors (TFs) and their co-factors involved in gene transcription regulation and showed gene interaction with Cytoscape.ConclusionThe biomarkers and canonical pathways identified in this study may hold the key to understanding the mechanisms of DCM pathobiology and providing new targets for the therapeutic effect of SPM against DCM by targeting abnormal immune response and signal transduction.

What Role do Mitochondria Have in Diastolic Dysfunction? Implications for Diabetic Cardiomyopathy and Heart Failure With Preserved Ejection Function.

Diastolic dysfunction is common to both diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). Although commonly attributed to increased fibrosis, alterations in mitochondrial function and associated Ca2+ handling may contribute to impaired cardiac function. With mitochondrial dysfunction, increased reactive oxygen species (ROS), inflammation, and decreased adenosine triphosphate/adenosine diphosphate ratio may lead to increased extracellular matrix and diminished contractile relaxation. In this article, we discuss recent research implicating deficient mitochondria-associated endoplasmic reticulum membranes (MAMs) as it relates to impaired metabolic function and what role that may have in diastolic dysfunction in diabetic cardiomyopathy. The contribution of mitochondrial dysfunction to diastolic dysfunction in HFpEF is less established, but equally credible based on preclinical studies. However, there are notable differences between diabetic cardiomyopathy and HFpEF. Recent evidence implicates impaired endoplasmic reticulum signaling, in particular the unfolded protein response (UPR), in the pathogenesis of HFpEF. With HFpEF, enhanced pressure on the mitochondrial "gas pedal" because of increased cytosolic Ca2+ may perturb mitochondrial homeostasis. For diabetic cardiomyopathy and HFpEF, a better understanding of how altered cellular ion and redox status affect mitochondrial function is needed. Finally, we discuss the implications that mitochondrial dysfunction may have in devising novel therapeutic strategies for diabetic cardiomyopathy and HFpEF.

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.