Development Of Diabetic Cardiomyopathy Research Articles

Diabetic Cardiomyopathy: Role of Cell Death, Exosomes, Fibrosis and Epicardial Adipose Tissue.

Diabetic cardiomyopathy (DCM) represents one of the typical complications associated with diabetes. It has been described as anomalies in heart function and structure, with consequent high morbidity and mortality. DCM development can be described by two stages; the first is characterized by left ventricular hypertrophy and diastolic dysfunction, and the second by heart failure (HF) with systolic dysfunction. The proposed mechanisms involve cardiac inflammation, advanced glycation end products (AGEs) and angiotensin II. Furthermore, different studies have focused their attention on cardiomyocyte death through the different mechanisms of programmed cell death, such as apoptosis, autophagy, necrosis, pyroptosis and ferroptosis. Exosome release, adipose epicardial tissue and aquaporins affect DCM development. This review will focus on the description of the mechanisms involved in DCM progression and development.

Diabetes cardiomyopathy: targeted regulation of mitochondrial dysfunction and therapeutic potential of plant secondary metabolites.

Diabetic cardiomyopathy (DCM) is a specific heart condition in diabetic patients, which is a major cause of heart failure and significantly affects quality of life. DCM is manifested as abnormal cardiac structure and function in the absence of ischaemic or hypertensive heart disease in individuals with diabetes. Although the development of DCM involves multiple pathological mechanisms, mitochondrial dysfunction is considered to play a crucial role. The regulatory mechanisms of mitochondrial dysfunction mainly include mitochondrial dynamics, oxidative stress, calcium handling, uncoupling, biogenesis, mitophagy, and insulin signaling. Targeting mitochondrial function in the treatment of DCM has attracted increasing attention. Studies have shown that plant secondary metabolites contribute to improving mitochondrial function and alleviating the development of DCM. This review outlines the role of mitochondrial dysfunction in the pathogenesis of DCM and discusses the regulatory mechanism for mitochondrial dysfunction. In addition, it also summarizes treatment strategies based on plant secondary metabolites. These strategies targeting the treatment of mitochondrial dysfunction may help prevent and treat DCM.

Research progress of traditional Chinese medicine in regulating autophagy for intervening in diabetic cardiomyopathy

Diabetic cardiomyopathy(DCM) is a chronic complication of diabetes mellitus that leads to cardiac damage in the later stages of the disease, and its pathogenesis is complex, involving metabolic disorders brought about by a variety of aberrant alterations such as endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis, defects in cardiomyocyte Ca~(2+) transporter, and myocardial fibrosis. Currently, there is a lack of specific diagnosis and treatment in the clinic. Autophagy is a highly conserved scavenging mechanism that removes proteins, damaged organelles or foreign contaminants and converts them into energy and amino acids to maintain the stability of the intracellular environment. Inhibition of autophagy can cause harmful metabolites to accumulate in the cell, while over-activation of autophagy can disrupt normal cellular structures and cause cell death. Prolonged high glucose levels disrupt cardiomyocyte autophagy levels and exacerbate the development of DCM. The protective or detrimental effects of autophagy on cells ring true with the traditional Chinese medicine theory of healthy Qi and pathogenic Qi. Autophagy in the physiological state of the removal of intracellular substances and the generation of substances beneficial to the survival of cells is the inhibition of pathogenic Qi to help the performance of healthy Qi, so the organism is healthy. In the early stages of the disease, when autophagy is impaired and incapable of removing waste substances, pathogenic Qi is prevalent; In the later stages of the disease, excessive activation of autophagy can destroy normal cells, leading to a weakening of healthy Qi. Traditional Chinese medicine has the advantage of targeting multiple sites and pathways. Studies in recent years have confirmed that traditional Chinese medicine monomers or formulas can target autophagy, promote the restoration of autophagy levels, maintain mitochondrial and endoplasmic reticulum homeostasis, and reduce oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis in order to prevent and control DCM. This study provides a review of the relationship between autophagy and DCM and the intervention of traditional Chinese medicine in autophagy for the treatment of DCM, with a view to providing new clinical ideas and methods for the treatment of DCM with traditional Chinese medicine.

Determining the Time Points for the Development of Early and Advanced Stages of Diabetic Cardiomyopathy in Streptozotocin-Induced Type 1 Diabetes Mellitus Rat Model

The characteristics of early and advanced stages of diabetic cardiomyopathy (DCM) are well-understood; however, the time points by which these stages are developed in animal models vary and depend on the hyperglycaemic status and duration of diabetes. This study was aimed to determine the time points for the development of early and advanced stages of DCM from the induction of type 1 diabetes mellitus by identifying the functional and histological changes that occurred. Type 1 diabetes was induced via streptozotocin injection, and rats were divided into 4-week and 8-week diabetic groups. A group of non-diabetic rats served as the normal control. Cardiac functions and structural changes were analysed. Results showed that after four weeks, all diabetic rats displayed early DCM characteristics, including pronounced left ventricular diastolic dysfunction and cardiomyocyte hypertrophy (P < 0.05) compared to the normal control. After eight weeks, there was a significant deterioration in both left ventricular systolic and diastolic function compared to the normal control, along with marked cardiomyocyte hypertrophy and myocardial fibrosis (P < 0.05), signifying the development of advanced DCM. In summary, this findings revealed the development of early and advanced stages of DCM at four weeks and eight weeks of diabetes respectively in diabetes melitus type 1 rat model.

The association between vitamin D and the progression of diabetic nephropathy: insights into potential mechanisms.

Vitamin D deficiency (VDD) is prevalent in the population, with inadequate intake, impaired absorption and metabolism as the main causative factors. VDD increases the risk of developing chronic diseases such as type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), but the molecular mechanisms underlying this phenomenon are not known. The aim of this study was to investigate the association and potential mechanisms of vitamin D levels with the progression of DN by analyzing general clinical data and using bioinformatics methods. The study included 567 diabetes mellitus type 2 (T2DM) patients from the Rocket Force Characteristic Medical Center as the case group and 221 healthy examinees as the normal control group. T2DM patients were categorized into T2DM, early diabetic nephropathy (EDN), and advanced diabetic nephropathy (ADN) based on the progression of diabetic nephropathy. The renal RNA-seq and scRNA-seq data of patients with DN were mined from public databases, and the differential expression of vitamin D-related genes in normal-EDN-ADN was analyzed by bioinformatics method, protein interaction network was constructed, immune infiltration was evaluated, single cell map was drawn, and potential mechanisms of VD and DN interaction were explored. Chi-square test showed that vitamin D level was significantly negatively correlated with DN progression (p < 0.001). Bioinformatics showed that the expression of vitamin D-related cytochrome P450 family genes was down-regulated, and TLR4 and other related inflammatory genes were abnormally up-regulated with the progression of DN. Vitamin D metabolism disturbance up-regulate "Nf-Kappa B signaling pathway," B cell receptor signaling pathway and other immune regulation and insulin resistance related pathways, and inhibit a variety of metabolic pathways. In addition, vitamin D metabolism disturbance are strongly associated with the development of diabetic cardiomyopathy and several neurological disease complications. VDD or vitamin D metabolism disturbance is positively associated with the severity of renal injury. The mechanisms may involve abnormal regulation of the immune system by vitamin D metabolism disturbance, metabolic suppression, upregulation of insulin resistance and inflammatory signalling pathways.

Roles of heat shock protein A12A in the development of diabetic cardiomyopathy.

Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not been fully elucidated. Heat shock protein A12A (HSPA12A) is the atypic member of the Heat shock 70kDa protein family. In the present study, we found that the expression of HSPA12A was upregulated in the hearts of mice with streptozotocin-induced diabetes, while ablation of HSPA12A improved cardiac systolic and diastolic dysfunction and increased cumulative survival of diabetic mice. An increased expression of HSPA12A was also found in H9c2 cardiac cells following treatment with high glucose (HG), while overexpression of HSPA12A-enhanced the HG-induced cardiac cell death, as reflected by higher levels of propidium iodide cells, lactate dehydrogenase leakage, and caspase 3 cleavage. Moreover, the HG-induced increase of oxidative stress, as indicated by dihydroethidium staining, was exaggerated by HSPA12A overexpression. Further studies demonstrated that the HG-induced increases of protein kinase B and forkhead box transcription factors 1 phosphorylation were diminished by HSPA12A overexpression, while pharmacologically inhibition of protein kinase B further enhanced the HG-induced lactate dehydrogenase leakage in HSPA12A overexpressed cardiac cells. Together, the results suggest that hyperglycemia upregulated HSPA12A expression in cardiac cells, by which induced cell death to promote DCM development. Targeting HSPA12A may serve as a potential approach for DCM management.

Myricetin alleviates diabetic cardiomyopathy by regulating gut microbiota and their metabolites

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

Chronic intermittent hypoxia aggravated diabetic cardiomyopathy through LKB1/AMPK/Nrf2 signaling pathway.

Chronic intermittent hypoxia (CIH) may play an important role in the development of diabetic cardiomyopathy (DCM). However, the exact mechanism of CIH-induced myocardial injury in DCM remains unclear. In vivo, the db/db mice exposed to CIH were established, and in vitro, the H9C2 cells were exposed to high glucose (HG) combined with intermittent hypoxia (IH). The body weight (BW), fasting blood glucose (FBG) and food intake were measured every two weeks. The glycolipid metabolism was assessed with the oral glucose tolerance test (OGTT) and insulin resistance (IR). Cardiac function was detected by echocardiography. Cardiac pathology was detected by HE staining, Masson staining, and transmission electron microscopy. The level of reactive oxygen species (ROS) in myocardial tissue was detected by dihydroethidium (DHE). The apoptosis was detected by TUNEL staining. The cell viability, ROS, and the mitochondrial membrane potential were detected by the cell counting kit-8 (CCK-8) assay and related kits. Western blotting was used to analyze the liver kinase B1/AMP-activated protein kinase/ nuclear factor-erythroid 2-related factor 2 (LKB1/AMPK/Nrf2) signaling pathway. CIH exposure accelerated glycolipid metabolism disorders and cardiac injury, and increased the level of cardiac oxidative stress and the number of positive apoptotic cells in db/db mice. IH and HG decreased the cell viability and the level of mitochondrial membrane potential, and increased ROS expression in H9C2 cells. These findings indicate that CIH exposure promotes glycolipid metabolism disorders and myocardial apoptosis, aggravating myocardial injury via the LKB1/AMPK/Nrf2 pathway in vitro and in vivo.

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.

Diabetic Cardiomyopathy and Cell Death: Focus on Metal-Mediated Cell Death.

Cardiac myocyte death is an essential initiator of the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), a disease that has been reported since 1972. Cardiac cell death has been detected in the hearts of patients with diabetes and in animal models, and the role of cell death in the pathogenesis of DCM has been extensively investigated. The first review by the authors, specifically focusing on "Cell death and diabetic cardiomyopathy," was published in the journal, Cardiovascular Toxicology in 2003. Over the past two decades, studies investigating the role of cardiac cell death in the pathogenesis of DCM have gained significant attention, resulting in the discovery of several new kinds of cell death involving different mechanisms, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. After the 20th anniversary of the review published in 2003, we now provide an update with a focus on the potential role of metal-mediated cell death, ferroptosis, and cuproptosis in the development of DCM in compliance with this special issue. The intent of our review is to further stimulate work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.

Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

Role of pyroptosis in diabetic cardiomyopathy: an updated review.

Diabetic cardiomyopathy (DCM), one of the common complications of diabetes, presents as a specific cardiomyopathy with anomalies in the structure and function of the heart. With the increasing prevalence of diabetes, DCM has a high morbidity and mortality worldwide. Recent studies have found that pyroptosis, as a programmed cell death accompanied by an inflammatory response, exacerbates the growth and genesis of DCM. These studies provide a theoretical basis for exploring the potential treatment of DCM. Therefore, this review aims to summarise the possible mechanisms by which pyroptosis promotes the development of DCM as well as the relevant studies targeting pyroptosis for the possible treatment of DCM, focusing on the molecular mechanisms of NLRP3 inflammasome-mediated pyroptosis, different cellular pyroptosis pathways associated with DCM, the effects of pyroptosis occurring in different cells on DCM, and the relevant drugs targeting NLRP3 inflammasome/pyroptosis for the treatment of DCM. This review might provide a fresh perspective and foundation for the development of therapeutic agents for DCM.

Role of epicardial adipose tissue in diabetic cardiomyopathy through the lens of cardiovascular magnetic resonance imaging - a narrative review.

Accumulating evidence suggests that ectopic/visceral adiposity may play a key role in the pathogenesis of nonischaemic cardiovascular diseases associated with type 2 diabetes. Epicardial adipose tissue (EAT) is a complex visceral fat depot, covering 80% of the cardiac surface with anatomical and functional contiguity to the myocardium and coronary arteries. EAT interacts with the biology of the underlying myocardium by secreting a wide range of adipokines. Magnetic resonance imaging (MRI) is the reference modality for structural and functional imaging of the heart. The technique is now also emerging as the reference imaging modality for EAT quantification. With this narrative review, we (a) surveyed contemporary clinical studies that utilized cardiovascular MRI to characterize EAT (studies published 2010-2023); (b) listed the clinical trials monitoring the response to treatment in EAT size as well as myocardial functional and structural parameters and (c) discussed the potential pathophysiological role of EAT in the development of diabetic cardiomyopathy. We concluded that increased EAT quantity and its inflammatory phenotype correlate with early signs of left ventricle dysfunction and may have a role in the pathogenesis of cardiac disease in diabetes with and without coronary artery disease.

PLIN5 Suppresses Lipotoxicity and Ferroptosis in Cardiomyocyte via Modulating PIR/NF-κB Axis.

Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe2+), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe2+/MDA/ROS, and expression of interleukin (IL)-1β/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.

Diabetic cardiomyopathy in rats was attenuated by endurance exercise through the inhibition of inflammation and apoptosis

Diabetic cardiomyopathy (DCM), as a ventricular dysfunction, is one of the main causes of death in diabetic patients. Former evidence revealed the beneficial effects of exercise on cardiovascular complications of diabetes. We aimed to investigate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on DCM. Male Wistar rats were divided into control, diabetic, metformin (300 mg/kg), HIIT, MICT, metformin + HIIT, and metformin + MICT diabetic groups. Serum biochemical, inflammatory, and oxidative stress indicators, gene expression of BCL2 and BAX, and histopathologic changes of cardiac tissue were assessed. Our analysis revealed an increase in fasting blood sugar (FBS), creatine kinase MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) in diabetes. Also, the superoxide dismutase (SOD) and catalase (CAT) activity, and the total thiol were decreased, in contrast, malondialdehyde (MDA) levels increased in the cardiac tissue of the diabetic group. All of these changes were significantly ameliorated in diabetic animals treated with exercise and metformin + exercise. The level of tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β), as well as the infiltration of inflammatory cells, were decreased in the heart of all exercise training groups. Up-regulation of BCL2 and down-regulation of BAX gene expressions were observed in the cardiac tissue of all exercise-treated groups. In conclusion, HIIT and MICT exercises are effective in preventing DCM development. Exercise training, besides improving oxidative stress and inflammation in cardiac tissue, alleviates cardiac damage by modulating the apoptotic gene expression in diabetic rats.

Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.

The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin-like modifier], a post-translational modification of proteins, and its associated ubiquitin-proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart. Specifically, the expression of ubiquitin-conjugating enzyme E2 (Ubc9), the only SUMO-E2 enzyme, exerts a positive regulatory effect on autophagy in cardiomyocytes with potential cardioprotective effects. This review focuses on the role that autophagy plays in DCM and the potential for Ubc9-regulated autophagy pathways to ameliorate DCM, highlighting the potential of Ubc9 as an interventional target in DCM and providing new insights into the pathogenesis of the disease.

Gasdermin D-Mediated Pyroptosis in Diabetic Cardiomyopathy: Molecular Mechanisms and Pharmacological Implications.

Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus (DM), which can lead to heart failure (HF). One of the most important cellular processes associated with DCM is the death of cardiomyocytes. Gasdermin D (GSDMD) plays a key role in mediating pyroptosis, a type of programmed cell death closely associated with inflammasome activation. Recent studies have revealed that pyroptosis is induced during hyperglycemia, which is crucial to the development of DCM. Although the effects of pyroptosis on DCM have been discussed, the relationship between DCM and GSDMD is not fully clarified. Recent studies gave us the impetus for clarifying the meaning of GSDMD in DCM. The purpose of this review is to summarize new and emerging insights, mainly discussing the structures of GSDMD and the mechanism of pore formation, activation pathways, molecular mechanisms of GSDMD-mediated pyroptosis, and the therapeutic potential of GSDMD in DCM. The implications of this review will pave the way for a new therapeutic target in DCM.

Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization.

The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.

FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control in diabetic cardiomyopathy.

To investigate the role of FOXO1 in STAT3 activation and mitochondrial quality control in the diabetic heart. Type 1 diabetes mellitus (T1DM) was induced in rats by a single intraperitoneal injection of 60 mg · kg-1 streptozotocin (STZ), while type 2 diabetes mellitus (T2DM) was induced in rats with a high-fat diet through intraperitoneal injection of 35 mg · kg-1 STZ. Primary neonatal mouse cardiomyocytes and H9c2 cells were exposed to low glucose (5.5 mM) or high glucose (HG; 30 mM) with or without treatment with the FOXO1 inhibitor AS1842856 (1 μM) for 24 hours. In addition, the diabetic db/db mice (aged 8 weeks) and sex- and age-matched non-diabetic db/+ mice were treated with vehicle or AS1842856 by oral gavage for 15 days at a dose of 5 mg · kg-1 · d-1 . Rats with T1DM or T2DM had excessive cardiac FOXO1 activation, accompanied by decreased STAT3 activation. Immunofluorescence and immunoprecipitation analysis showed colocalization and association of FOXO1 and STAT3 under basal conditions in isolated cardiomyocytes. Selective inhibition of FOXO1 activation by AS1842856 or FOXO1 siRNA transfection improved STAT3 activation, mitophagy and mitochondrial fusion, and decreased mitochondrial fission in isolated cardiomyocytes exposed to HG. Transfection with STAT3 siRNA further reduced mitophagy, mitochondrial fusion and increased mitochondrial fission in HG-treated cardiomyocytes. AS1842856 alleviated cardiac dysfunction, pathological damage and improved STAT3 activation, mitophagy and mitochondrial dynamics in diabetic db/db mice. Additionally, AS1842856 improved mitochondrial function indicated by increased mitochondrial membrane potential and adenosine triphosphate production and decreased mitochondrial reactive oxygen species production in isolated cardiomyocytes exposed to HG. Excessive FOXO1 activation during diabetes reduces STAT3 activation, with subsequent impairment of mitochondrial quality, ultimately promoting the development of diabetic cardiomyopathy.

Abstract 12317: UBC9 Alleviates Diabetic Cardiomyopathy via the Modulation of Mitophagy

Introduction: Type 2 diabetes is prevalent worldwide. Cardiovascular complications in patients with diabetes include diabetic cardiomyopathy (DCM). Ubiquitin-conjugating enzyme E2 I (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes. Hypothesis: The present study aimed to elucidate the role and mechanism of action of UBC9 in the development of DCM. Methods: We established myocardial-specific UBC9 knockout (UBC9-CKO) and adeno-associated virus-overexpressing mouse models. Additionally, a mouse model of DCM was established using high-fat diet feeding and low-dose streptozotocin injection. This mechanism was explained by the stimulation of cultured cardiomyocytes with palmitic acid. Results: The transcript and protein levels of UBC9 were significantly decreased in the myocardium of patients with DCM. Myocardial-specific UBC9 knockout aggravated cardiac dysfunction, alleviated myocardial fibrosis and hypertrophy, and promoted mitophagy and mitochondrial damage. Meanwhile, UBC9 overexpression exhibited the opposite effects. UBC9 exerted mitochondrial protective effects independent of SUMOylation. UBC9 regulated RUNX2 degradation by directly binding to NEDD4, thus regulating PSEN2 to exert protective effects against mitophagy. Moreover, the effect of UBC9 on mitochondrial function was reversed upon PSEN2 knockdown. Conclusions: UBC9 regulates mitophagy through the NEDD4/RUNX2/PSEN2 pathway and alleviates DCM development by improving myocardial mitochondrial dysfunction. These findings offer novel perspectives on the application of UBC9 as a therapeutic target for DCM.