Pathogenesis Of Diabetic Cardiomyopathy Research Articles

Ferroptosis in diabetic cardiomyopathy: from its mechanisms to therapeutic strategies

Diabetic cardiomyopathy (DCM) is defined as structural and functional cardiac abnormalities in diabetes, and cardiomyocyte death is the terminal event of DCM. Ferroptosis is iron-dependent oxidative cell death. Evidence has indicated that iron overload and ferroptosis play important roles in the pathogenesis of DCM. Mitochondria, an important organelle in iron homeostasis and ROS production, play a crucial role in cardiomyocyte ferroptosis in diabetes. Studies have shown some anti-diabetic medicines, plant extracts, and ferroptosis inhibitors might improve DCM by alleviating ferroptosis. In this review, we systematically reviewed the evidence of ferroptosis in DCM. Anti-ferroptosis might be a promising therapeutic strategy for the treatment of DCM.

Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron-sulfur (Fe-S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S-sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H2S) supplementation restores NFS1 S-sulfhydration at cysteine 383 residue, thereby enhancing Fe-S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe-S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes.

N6-methyladenosine modification of SPOP relieves ferroptosis and diabetic cardiomyopathy by enhancing ubiquitination of VDAC3.

Understanding the pathogenesis of diabetic cardiomyopathy (DCM), a common microvascular complication affecting the heart, is crucial for identifying new therapeutic targets and intervention strategies for DCM. Our study revealed a significant downregulation in Speckle-type POZ protein (SPOP) expression in DCM, while the overexpression of SPOP improved DCM-induced myocardial dysfunction, injury, fibrosis, hypertrophy, and ferroptosis. Mechanistically, SPOP facilitated the degradation of voltage-dependent anion channel 3 (VDAC3) by enhancing its ubiquitination. M6A demethylase AlkB homolog 5 (ALKBH5) reduced the mRNA stability of SPOP by decreasing m6A modification in its 3'UTR. The m6A reader insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) enhanced the stability of SPOP mRNA through recognition of m6A-modified SPOP 3'UTR. Furthermore, ALKBH5 promoted ferroptosis by inhibiting SPOP-induced VDAC3 degradation, while IGF2BP2 inhibited ferroptosis via activation of SPOP-induced VDAC3 degradation in high glucose-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Overall, our study has unveiled a novel role of SPOP in the pathogenesis of ferroptosis and DCM, thereby significantly advancing our understanding of the involvement of ferroptosis during the progression of DCM. Moreover, this discovery offers promising potential therapeutic interventions targeting DCM.

Identification of immune feature genes and intercellular profiles in diabetic cardiomyopathy

BACKGROUND Diabetic cardiomyopathy (DCM) is a multifaceted cardiovascular disorder in which immune dysregulation plays a pivotal role. The immunological molecular mechanisms underlying DCM are poorly understood. AIM To examine the immunological molecular mechanisms of DCM and construct diagnostic and prognostic models of DCM based on immune feature genes (IFGs). METHODS Weighted gene co-expression network analysis along with machine learning methods were employed to pinpoint IFGs within bulk RNA sequencing (RNA-seq) datasets. Single-sample gene set enrichment analysis (ssGSEA) facilitated the analysis of immune cell infiltration. Diagnostic and prognostic models for these IFGs were developed and assessed in a validation cohort. Gene expression in the DCM cell model was confirmed through real time-quantitative polymerase chain reaction and western blotting techniques. Additionally, single-cell RNA-seq data provided deeper insights into cellular profiles and interactions. RESULTS The overlap between 69 differentially expressed genes in the DCM-associated module and 2483 immune genes yielded 7 differentially expressed immune-related genes. Four IFGs showed good diagnostic and prognostic values in the validation cohort: Proenkephalin (Penk) and retinol binding protein 7 (Rbp7), which were highly expressed, and glucagon receptor and inhibin subunit alpha, which were expressed at low levels in DCM patients (all area under the curves > 0.9). SsGSEA revealed that IFG-related immune cell infiltration primarily involved type 2 T helper cells. High expression of Penk (P < 0.0001) and Rbp7 (P = 0.001) was detected in cardiomyocytes and interstitial cells and further confirmed in a DCM cell model in vitro . Intercellular events and communication analysis revealed abnormal cellular phenotype transformation and signaling communication in DCM, especially between mesenchymal cells and macrophages. CONCLUSION The present study identified Penk and Rbp7 as potential DCM biomarkers, and aberrant mesenchymal-immune cell phenotype communication may be an important aspect of DCM pathogenesis.

Fibroblast-specific TGF-β signaling mediates cardiac dysfunction, fibrosis, and hypertrophy in obese diabetic mice.

Transforming growth factor (TGF)-β is up-regulated in the diabetic myocardium and may mediate fibroblast activation. We aimed at examining the role of TGF-β-induced fibroblast activation in the pathogenesis of diabetic cardiomyopathy. We generated lean and obese db/db mice with fibroblast-specific loss of TbR2, the Type 2 receptor-mediating signaling through all three TGF-β isoforms, and mice with fibroblast-specific Smad3 disruption. Systolic and diastolic function, myocardial fibrosis, and hypertrophy were assessed. Transcriptomic studies and in vitro experiments were used to dissect mechanisms of fibroblast activation. Fibroblast-specific TbR2 loss attenuated systolic and diastolic dysfunction in db/db mice. The protective effects of fibroblast TbR2 loss in db/db mice were associated with attenuated fibrosis and reduced cardiomyocyte hypertrophy, suggesting that in addition to their role in fibrous tissue deposition, TGF-β-stimulated fibroblasts may also exert paracrine actions on cardiomyocytes. Fibroblast-specific Smad3 loss phenocopied the protective effects of fibroblast TbR2 loss in db/db mice. Db/db fibroblasts had increased expression of genes associated with oxidative response (such as Fmo2, encoding flavin-containing monooxygenase 2), matricellular genes (such as Thbs4 and Fbln2), and Lox (encoding lysyl oxidase). Ingenuity pathway analysis (IPA) predicted that neurohumoral mediators, cytokines, and growth factors (such as AGT, TGFB1, and TNF) may serve as important upstream regulators of the transcriptomic profile of diabetic mouse fibroblasts. IPA of scRNA-seq data identified TGFB1, p53, MYC, PDGF-BB, EGFR, and WNT3A/CTNNB1 as important upstream regulators underlying fibroblast activation in db/db hearts. Comparison of the transcriptome of fibroblasts from db/db mice with fibroblast-specific Smad3 loss and db/db Smad3 fl/fl controls identified Thbs4 [encoding thrombospondin-4 (TSP-4), a marker of activated fibroblasts] as a candidate diabetes-induced fibrogenic mediator. However, in vitro experiments showed no significant activating effects of matricellular or intracellular TSP-4 on cardiac fibroblasts. Fibroblast-specific TGF-β/Smad3 signaling mediates ventricular fibrosis, hypertrophy, and dysfunction in Type 2 diabetes.

TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway.

Diabetic cardiomyopathy (DCM) is identified as a progressive disease that may lead to irreparable heart failure. Toll-like receptor (TLR) signaling is believed to be implicated in the pathogenesis of DCM. This study intended to explore the potential impact of Toll-like receptor 4 (TLR4) on DCM in vitro and in vivo. Streptozotocin and HG medium were utilized to induce diabetes in animal and cell models, respectively. Selective TLR4 inhibitor TAK-242 and calcium/calmodulin-dependent protein kinase-II (CaMKII) inhibitor KN-93 were employed to explore the involvement of TLR4/CaMKII in DCM. TLR4 expression was increased in DCM hearts, while inhibition of TLR4 activation by TAK-242 improved cardiac function, attenuated heart hypertrophy, and fibrosis, as well as reduced oxidative stress and proinflammatory cytokine levels in rats, which were confirmed by Doppler echocardiography, hematoxylin and eosin staining, and Masson Trichome staining and specific enzyme-linked immunosorbent assay kits. Besides, the expression of hypertrophy-related molecules and oxidative stress damage were also inhibited by TAK-242. Furthermore, TAK-242 treatment reduced CaMKII phosphorylation accompanied by decreased expression of NOD-like pyrin domain-containing protein 3, gasdermin D (GSDMD), The N-terminal domain of Gasdermin D (GSDMD-N), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and Caspase-1 both in vivo and in vitro. Similar positive impacts on HG-induced pyroptosis were also observed with KN-93 treatment, and this was achieved without affecting TLR4 expression. Collectively, our work suggested that TAK-242 demonstrated substantial benefits against DCM both in vivo and in vitro, potentially attributed to the suppression of the TLR4-mediated CaMKII/NLRP3 pathway activity.

LARP7 Contributes to Glucose-Induced Cardiac Dysfunction, Apoptosis and Fibrosis by Inhibiting the Degradation of STING.

Diabetic cardiomyopathy (DCM) is an important cause of heart failure in diabetic patients. The aim of this study was to investigate the pathogenesis of DCM and to identify potential therapeutic targets. A mouse model of type 1 DCM was constructed by continuous intraperitoneal injection of streptozotocin (STZ). Systolic and diastolic functions were measured by ultrasound. The expression of La-related protein 7 (LARP7), the stimulator of interferon genes (STING) pathway and light chain 3 (LC3) in myocardial tissue was detected by Western blot and immunofluorescence analyses. Neonatal mouse ventricular cardiomyocytes (NMVCMs) were isolated and cultured. An in vitro type 1 diabetes mellitus (T1DM) model was established by treatment with high glucose. Knockdown/overexpression of LARP7 and STING was achieved by adenovirus transduction, C-176 (a potent covalent inhibitor of STING), and plasmid transfection. The expression, activation, and localization of STING and LARP7 in cardiomyocytes was evaluated, as well as the interaction between the two. The effect of this interaction on the STING-dependent autophagy‒lysosomal pathway was also explored. In addition, the fibrosis and apoptosis of cardiomyocytes were evaluated. High glucose was found to increase the expression and activation of STING and LARP7 in mouse myocardial tissue. This was accompanied by myocardial fibrosis, impaired autophagy degradation function and impaired cardiac function. These findings were further confirmed by in vitro experiments. High glucose caused LARP7 to translocate from the nucleus to the cytoplasm, where it interacted with accumulated STING to inhibit its degradation. Inhibition of STING or LARP7 expression significantly improved myocardial injury induced by high glucose. Targeted inhibition of LARP7 or STING expression may be a potential therapeutic strategy for the treatment of DCM.

Uncovering the Therapeutic Potential of Lithium Chloride in Type 2 Diabetic Cardiomyopathy: Targeting Tau Hyperphosphorylation and TGF-β Signaling via GSK-3β Inhibition.

Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role of tauopathy in myocardial dysfunction observed in T2DM. In that regard, diabetic Sprague Dawley rats were treated with intraperitoneal injections of lithium chloride (LiCl), inhibiting tau phosphorylation. Cardiac function was evaluated, and molecular markers of myocardial fibrosis and the TGF-β signaling were analyzed. T2DM rats exhibited a decline in ejection fraction and fractional shortening that revealed cardiac function abnormalities and increased myocardial fibrosis. These changes were associated with tau hyperphosphorylation. Treating diabetic rats with LiCl attenuated cardiac fibrosis and improved myocardial function. Inhibition of GSK-3β leads to the suppression of tau phosphorylation, which is associated with a decrease in TGF-β expression and regulation of the pro-inflammatory markers, suggesting that tau hyperphosphorylation is parallelly associated with fibrosis and inflammation in the diabetic heart. Our findings provide evidence of a possible role of tau hyperphosphorylation in the pathogenesis of DCM through the activation of TGF-β and by inducing inflammation. Targeting the inhibition of tau phosphorylation may offer novel therapeutic approaches to reduce DCM burden in T2DM patients.

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.

Atorvastatin ameliorated myocardial fibrosis by inhibiting oxidative stress and modulating macrophage polarization in diabetic cardiomyopathy

In this editorial, we commented on the article published in the recent issue of the World Journal of Diabetes . Diabetic cardiomyopathy (DCM) is characterized by myocardial fibrosis, ventricular hypertrophy and diastolic dysfunction in diabetic patients, which can cause heart failure and threaten the life of patients. The pathogenesis of DCM has not been fully clarified, and it may involve oxidative stress, inflammatory stimulation, apoptosis, and autophagy. There is lack of effective therapies for DCM in the clinical practice. Statins have been widely used in the clinical practice for years mainly to reduce cholesterol and stabilize arterial plaques, and exhibit definite cardiovascular protective effects. Studies have shown that statins also have anti-inflammatory and antioxidant effects. We were particularly concerned about the recent findings that atorvastatin alleviated myocardial fibrosis in db/db mice by regulating the antioxidant stress and anti-inflammatory effects of macrophage polarization on diabetic myocardium, and thereby improving DCM.

Histone acetyltransferase Kat2a regulates ferroptosis via enhancing Tfrc and Hmox1 expression in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM can significantly contribute to enhancing its prevention and treatment strategies. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Functionally, inhibition of Kat2a effectively ameliorated high glucose-induced cardiomyocyte injury both in vitro and in vivo by suppressing ferroptosis. Mechanistically, Demethylase alkB homolog 5 (Alkbh5) was found to reduce m6A methylation levels on Kat2a mRNA, leading to its upregulation. YTH domain family 2 (Ythdf2) played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing Tfrc and Hmox1 expression via enhancing the enrichment of H3K27ac and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.

Combination of ADAM17 knockdown with eplerenone is more effective than single therapy in ameliorating diabetic cardiomyopathy.

The renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM). Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers combined with aldosterone receptor antagonists (mineralocorticoid receptor antagonists) have substantially improved clinical outcomes in patients with DCM. However, the use of the combination has been limited due to its high risk of inducing hyperkalemia. Type 1 diabetes was induced in 8-week-old male C57BL/6J mice by intraperitoneal injection of streptozotocin at a dose of 55mg/kg for 5 consecutive days. Adeno-associated virus 9-mediated short-hairpin RNA (shRNA) was used to knock down the expression of ADAM17 in mice hearts. Eplerenone was administered via gavage at 200mg/kg daily for 4weeks. Primary cardiac fibroblasts were exposed to high glucose (HG) in vitro for 24h to examine the cardiac fibroblasts to myofibroblasts transformation (CMT). Cardiac collagen deposition and CMT increased in diabetic mice, leading to cardiac fibrosis and dysfunction. In addition, ADAM17 expression and activity increased in the hearts of diabetic mice. ADAM17 inhibition and eplerenone treatment both improved diabetes-induced cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction, ADAM17 deficiency combined with eplerenone further reduced the effects of cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction compared with single therapy in vivo. High-glucose stimulation promotes CMT in vitro and leads to increased ADAM17 expression and activity. ADAM17 knockdown and eplerenone pretreatment can reduce the CMT of fibroblasts that is induced by high glucose levels by inhibiting TGFβ1/Smad3 activation; the combination of the two can further reduce CMT compared with single therapy in vitro. Our findings indicated that ADAM17 knockout could improve diabetes-induced cardiac dysfunction and remodeling through the inhibition of RAAS overactivation when combined with eplerenone treatment, which reduced TGF-β1/Smad3 pathway activation-mediated CMT. The combined intervention of ADAM17 deficiency and eplerenone therapy provided additional cardiac protection compared with a single therapy alone without disturbing potassium level. Therefore, the combination of ADAM17 inhibition and eplerenone is a potential therapeutic strategy for human DCM.

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.

Interplay between Senescence and Macrophages in Diabetic Cardiomyopathy: A Review of the Potential Role of GDF-15 and Klotho.

Type 2 diabetes mellitus (T2DM) is a critical health problem, with 700 million diagnoses expected worldwide by 2045. Uncontrolled high blood glucose levels can lead to serious complications, including diabetic cardiomyopathy (DCM). Diabetes induces cardiovascular aging and inflammation, increasing cardiomyopathy risk. DCM is characterized by structural and functional abnormalities in the heart. Growing evidence suggests that cellular senescence and macrophage-mediated inflammation participate in the pathogenesis and progression of DCM. Evidence indicates that growth differentiation factor-15 (GDF-15), a protein that belongs to the transforming growth factor-beta (TGF-β) superfamily, is associated with age-related diseases and exerts an anti-inflammatory role in various disease models. Although further evidence suggests that GDF-15 can preserve Klotho, a transmembrane antiaging protein, emerging research has elucidated the potential involvement of GDF-15 and Klotho in the interplay between macrophages-induced inflammation and cellular senescence in the context of DCM. This review explores the intricate relationship between senescence and macrophages in DCM while highlighting the possible contributions of GDF-15 and Klotho.

MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus

Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options. While lactate, a byproduct of glycolysis, is known to be significantly elevated in type 2 diabetes, its specific role in DCM remains uncertain. This study reveals an abnormal upregulation of monocarboxylate transporter 4 (MCT4) on the plasma membrane of cardiomyocytes in type 2 diabetes, leading to excessive lactate efflux from these cells. The disruption in lactate transport homeostasis perturbs the intracellular lactate-pyruvate balance in cardiomyocytes, resulting in oxidative stress and inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased lactate efflux augments histone H4K12 lactylation in macrophages, facilitating inflammatory infiltration within the microenvironment. In vivo experiments have demonstrated that inhibiting MCT4 effectively alleviates myocardial oxidative stress and pathological damage, reduces inflammatory macrophage infiltration, and enhances cardiac function in type 2 diabetic mice. Furthermore, a clinical prediction model has been established, demonstrating a notable association between peripheral blood lactate levels and diastolic dysfunction in individuals with type 2 diabetes. This underscores the potential of lactate as a prognostic biomarker for DCM. Ultimately, our findings highlight the pivotal involvement of MCT4 in the dysregulation of cardiac energy metabolism and macrophage-mediated inflammation in type 2 diabetes. These insights offer novel perspectives on the pathogenesis of DCM and pave the way for the development of targeted therapeutic strategies against this debilitating condition.

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.

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.

Cardioprotective and Hypolipidemic Effect of Cardamom Oil-Loaded Lipid Carrier Nanoparticles in a Rat Model of Streptozotocin-Induced Diabetes

Background: Diabetic cardiomyopathy (DCM) is a serious complication of poorly managed diabetes. Inflammation, hyperglycemia, oxidative stress, hyperlipidemia, and other factors all play a role in DCM pathogenesis. Objective: To investigate the cardioprotective effects of cardamom oil-loaded lipid carrier nanoparticles (CEO-LC NPs) on streptozotocin (STZ)-induced diabetes in rats. Methods: Twenty-four male rats were randomly divided into four groups of six each. STZ (50 mg/kg) caused diabetes in all groups but the negative control. The diabetic control group (G1) received a normal saline solution. For 28 days, group G2 received CEO-LC NPs (600 mg/kg), group G3 received empagliflozin (10 mg/kg), and group G4 (no diabetes) received normal saline as a negative control. On day 29, blood samples were taken to determine blood glucose, cholesterol, LDL, HDL, and triglyceride levels, as well as oxidative stress markers. Additionally, atherogenic indices were calculated. Heart tissue was sent for histopathological examination. Results: In diabetic rats treated with CEO-LC NPs, serum glucose, cholesterol, LDL, and triglyceride levels were significantly reduced, while HDL levels increased. The CEO-LC NP treatment also reduced oxidative stress by increasing total antioxidant capacity while decreasing malondialdehyde (MDA). Furthermore, diabetic rats treated with CEO-LC NP had significantly lower AIP, CRI-I, and CRI-II ratios. Conclusions: CEO-LC NPs improve cardioprotection in STZ-induced diabetic rats by lowering plasma lipid levels and oxidative stress.

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.

The study of the mechanism of non-coding RNA regulation of programmed cell death in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) represents a distinct myocardial disorder elicited by diabetes mellitus, characterized by aberrations in myocardial function and structural integrity. This pathological condition predominantly manifests in individuals with diabetes who do not have concurrent coronary artery disease or hypertension. An escalating body of scientific evidence substantiates the pivotal role of programmed cell death (PCD)-encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis-in the pathogenic progression of DCM, thereby emerging as a prospective therapeutic target. Additionally, numerous non-coding RNAs (ncRNAs) have been empirically verified to modulate the biological processes underlying programmed cell death, consequently influencing the evolution of DCM. This review systematically encapsulates prevalent types of PCD manifest in DCM as well as nascent discoveries regarding the regulatory influence of ncRNAs on programmed cell death in the pathogenesis of DCM, with the aim of furnishing novel insights for the furtherance of research in PCD-associated disorders relevant to DCM.