Progression Of Diabetic Cardiomyopathy Research Articles

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

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

Progression of Diabetic cardiomyopathy among Type 2 Diabetic Patients: A Review Article

Progression of Diabetic cardiomyopathy among Type 2 Diabetic Patients: A Review Article

CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction

BackgroundThe progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated.MethodsCardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis and functional experiments.ResultsOur findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10.ConclusionsThe current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

Single-cell insights: pioneering an integrated atlas of chromatin accessibility and transcriptomic landscapes in diabetic cardiomyopathy

BackgroundDiabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM’s unique cell states and molecular landscape for targeted therapeutic interventions.MethodsSingle-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings.ResultsThis study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation.ConclusionOur integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.

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.

Construction and analysis of a network of exercise-induced mitochondria-related non-coding RNA in the regulation of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a major factor in the development of heart failure. Mitochondria play a crucial role in regulating insulin resistance, oxidative stress, and inflammation, which affect the progression of DCM. Regular exercise can induce altered non-coding RNA (ncRNA) expression, which subsequently affects gene expression and protein function. The mechanism of exercise-induced mitochondrial-related non-coding RNA network in the regulation of DCM remains unclear. This study seeks to construct an innovative exercise-induced mitochondrial-related ncRNA network. Bioinformatic analysis of RNA sequencing data from an exercise rat model identified 144 differentially expressed long non-coding RNA (lncRNA) with cutoff criteria of p< 0.05 and fold change ≥1.0. GSE6880 and GSE4745 were the differentially expressed mRNAs from the left ventricle of DCM rat that downloaded from the GEO database. Combined with the differentially expressed mRNA and MitoCarta 3.0 dataset, the mitochondrial located gene Pdk4 was identified as a target gene. The miRNA prediction analysis using miRanda and TargetScan confirmed that 5 miRNAs have potential to interact with the 144 lncRNA. The novel lncRNA-miRNA-Pdk4 network was constructed for the first time. According to the functional protein association network, the newly created exercise-induced ncRNA network may serve as a promising diagnostic marker and therapeutic target, providing a fresh perspective to understand the molecular mechanism of different exercise types for the prevention and treatment of diabetic cardiomyopathy.

Pharmacological Inhibition of Succinyl Coenzyme A:3-Ketoacid Coenzyme A Transferase Alleviates the Progression of Diabetic Cardiomyopathy.

Pharmacological Inhibition of Succinyl Coenzyme A:3-Ketoacid Coenzyme A Transferase Alleviates the Progression of Diabetic Cardiomyopathy.

Post-translational modifications in diabetic cardiomyopathy.

The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria and targeted treatment approaches in clinical practice. Ongoing research is gradually unravelling the pathogenesis of diabetic cardiomyopathy, with a particular emphasis on investigating various post-translational modifications. These modifications dynamically regulate protein function in response to changes in the internal and external environment, and their disturbance of homeostasis holds significant relevance for the development of chronic ailments. This review provides a comprehensive overview of the common post-translational modifications involved in the initiation and progression of diabetic cardiomyopathy, including O-GlcNAcylation, phosphorylation, methylation, acetylation and ubiquitination. Additionally, the review discusses drug development strategies for targeting key post-translational modification targets, such as agonists, inhibitors and PROTAC (proteolysis targeting chimaera) technology that targets E3 ubiquitin ligases.

USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

TRPM2 knockdown attenuates myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice via regulating the MEK/ERK and mTORC1 signaling pathway.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes. Transient receptor potential melastatin 2 (TRPM2) activity increases in diabetic oxidative stress state, and it is involved in myocardial damage and repair. We explore the protective effect of TRPM2 knockdown on the progression of DCM. A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100-mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in heart was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 9 carrying TRPM2 shRNA. Neonatal rat ventricular myocytes was exposed to 45mM of high-glucose (HG) stimulation for 72h in vitro to mimic the in vivo conditions. Western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry and fluorescence, electron, CCK-8, and flow cytometry were used to evaluate the phenotype of cardiac inflammation, fibrosis, apoptosis, and autophagy. Mice with HFD/STZ-induced diabetes exhibited systolic and diastolic dysfunction, as demonstrated by increased myocardial apoptosis and autophagy inhibition in the heart. Compared to control group, the protein expression of TRPM2, bax, cleaved caspase-3, and P62 was significantly elevated, and the protein expression of bcl-2 and LC3-II was significantly decreased in the myocardial tissues of the HFD/STZ-induced diabetes group. Knockdown of TRPM2 significantly reversed the HFD/STZ-induced myocardial apoptosis and autophagy inhibition. TRPM2 silencing attenuated HG-induced apoptosis and autophagy inhibition in primary cardiomyocytes via regulating the MEK/ERK mTORC1 signaling pathway. TRPM2 knockdown attenuates hyperglycemia-induced myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice or HG-stimulated cardiomyocytes via regulating the MEK/ERK and mTORC1 signaling pathway.

Nrf2 prevents diabetic cardiomyopathy via antioxidant effect and normalization of glucose and lipid metabolism in the heart.

Metabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. Here, we investigated in a cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) the direct effect of Nrf2 on cardiomyocytes in DCM and its mechanism. In this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. Compared to wild-type mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. These results showed that Nrf2 can directly act on cardiomyocytes to exert a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by directly targeting lipid metabolic pathway of AMPK/Sirt1/PGC-1α activation via upstream genes of sestrin2 and LKB1, and indirectly enabling AKT/GSK-3β/HK-Ⅱ activity via AMPK mediated p70S6K inhibition.

LncRNA HCG18 affects diabetic cardiomyopathy and its association with miR-9-5p/IGF2R axis

This paper aimed to investigate the role of lncRNA HCG18 (HCG18) in the progression of diabetic cardiomyopathy (DCM) and potential mechanisms. Streptozocin (STZ) was used to induce DCM model in rats, which was confirmed by blood glucose concentration, body weight, and HE staining. Myocardial apoptosis was detected by TUNEL. H9c2 cardiomyocytes were used to construct cell models of DCM through treatment of high glucose. The results showed that HCG18 was overexpressed in STZ induced DCM rat model and high glucose induced H9c2 cardiomyocytes. Si-HCG18 significantly increased cell viability, reduced cell apoptosis, attenuated activities of myocardial enzymes and enhanced activities of antioxidant enzymes in STZ induced DM model and high glucose induced H9c2 cardiomyocytes, while the results of upregulation of HCG18, in high glucose induced H9c2 cardiomyocytes, were opposite with that of si-HCG18. MiR-9-5p was a target of HCG18, and which was down-regulated in cardiomyocytes of DCM. The overexpression of miR-9-5p could neutralize the high glucose induced cardiomyocyte injury, and the silence of miR-9-5p could reverse the effect of si-HCG18 on high glucose induced cardiomyocytes. MiR-9-5p could directly target to IGF2R, and IGF2R was overexpressed in cardiomyocytes of DCM. Up-regulation of IGF2R can reverse the protective effect of si-HCG18 on cardiomyocytes. Taken together, HCG18 is significantly increased in cardiomyocytes of DCM. Down-regulation of HCG18 can improve cardiomyocyte injury through miR-9-5p/IGF2R axis in DCM.

The role of exosomes and exosomal microRNA in diabetic cardiomyopathy.

Diabetic cardiomyopathy, a formidable cardiovascular complication linked to diabetes, is witnessing a relentless surge in its incidence. Despite extensive research efforts, the primary pathogenic mechanisms underlying this condition remain elusive. Consequently, a critical research imperative lies in identifying a sensitive and dependable marker for early diagnosis and treatment, thereby mitigating the onset and progression of diabetic cardiomyopathy (DCM). Exosomes (EXOs), minute vesicles enclosed within bilayer lipid membranes, have emerged as a fascinating frontier in this quest, capable of transporting a diverse cargo that mirrors the physiological and pathological states of their parent cells. These exosomes play an active role in the intercellular communication network of the cardiovascular system. Within the realm of exosomes, MicroRNA (miRNA) stands as a pivotal molecular player, revealing its profound influence on the progression of DCM. This comprehensive review aims to offer an introductory exploration of exosome structure and function, followed by a detailed examination of the intricate role played by exosome-associated miRNA in diabetic cardiomyopathy. Our ultimate objective is to bolster our comprehension of DCM diagnosis and treatment strategies, thereby facilitating timely intervention and improved outcomes.

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.

Chinese Medicine Supplementing Qi and Activating Blood Circulation Relieves the Progression of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is the leading cause of diabetic death as the final occurrence of heart failure and arrhythmia. Traditional Chinese medicine is usually used to treat various diseases including diabetes. This study sought to investigate the effects of Traditional Chinese medicine supplementing Qi and activating blood circulation (SAC) in DCM. After the construction of the DCM model by streptozotocin (STZ) injection and high glucose/fat diet feeding, rats were administered intragastrically with SAC. Then, cardiac systolic/diastolic function was evaluated by detecting left ventricular systolic pressure (LVSP), maximal rate of left ventricular pressure rise (+LVdp/dtmax), and fall (-LVdp/dtmax), heart rate (HR), left ventricular ejection fraction (EF), LV fractional shortening (FS) and left ventricular end-diastolic pressure (LVEDP). Masson's and TUNEL staining were used to assess fibrosis and cardiomyocyte apoptosis. DCM rats exhibited impaired cardiac systolic/diastolic function manifested by decreasing LVSP, + LVdp/dtmax, -LVdp/dtmax, HR, EF and FS, and increasing LVEDP. Intriguingly, traditional Chinese medicine SAC alleviated the above-mentioned symptoms, indicating a potential role in improving cardiac function. Masson's staining substantiated that SAC antagonized the increased collagen deposition and interstitial fibrosis area and the elevations in protein expression of fibrosisrelated collagen I and fibronectin in heart tissues of DCM rats. Furthermore, TUNEL staining confirmed that traditional Chinese medicine SAC also attenuated cardiomyocyte apoptosis in DCM rats. Mechanically, DCM rats showed the aberrant activation of the TGF-β/Smad signaling, which was inhibited after SAC. SAC may exert cardiac protective efficacy in DCM rats via the TGF-β/Smad signaling, indicating a new promising therapeutic approach for DCM.

Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway.

Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear. To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism. Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels. In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes. Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.

Rev-erbα attenuates diabetic myocardial injury through regulation of ferroptosis

Diabetes is a widespread disease that threatens the life and health of human beings, and diabetic cardiomyopathy (DCM) is one of the major complications of diabetic patients. The pathological mechanisms of DCM are complex, including inflammation, endoplasmic reticulum stress, and oxidative stress that have been reported previously. Although recent studies suggested that ferroptosis is also involved in the progression of DCM, the exact mechanism remains unclear. Rev-erbα cardiac conditional knockout mice were generated and type 2 diabetes were induced by high fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ) in in vivo experiments. In parallel, our in vitro experiments entailed the introduction of elevated levels of glucose (HG) and palmitic acid (PA) to induce glycolipid toxicity in H9c2 cardiomyocytes. Further deterioration of cardiac function was detected by echocardiography after the clock gene rev-erbα was knocked out. This was accompanied by significant elevations in markers of inflammation, myocardial fibrosis, and oxidative stress. In addition, iron content, transmission electron microscopy (TEM), and RT-PCR assays confirmed significantly increased levels of ferroptosis in rev-erbα-deficient DCM. Intriguingly, Co-Immunoprecipitation (Co-IP) data uncovered an interaction between rev-erbα and nuclear factor E2-related factor 2 (NRF2) in diabetic myocardial tissues. It is worth highlighting that ferroptosis within cardiomyocytes witnessed significant mitigation upon the administration of sulforaphane (SFN), an NRF2 agonist, to HG + PA-incubated H9c2 cells. Our study demonstrates for the first time that knockdown of the clock gene rev-erbα exacerbates myocardial injury and ferroptosis in type 2 diabetic mice, which can be reversed by activating NRF2.

A gene therapy targeting medium-chain acyl-CoA dehydrogenase (MCAD) did not protect against diabetes-induced cardiac pathology.

Diabetic cardiomyopathy describes heart disease in patients with diabetes who have no other cardiac conditions but have a higher risk of developing heart failure. Specific therapies to treat the diabetic heart are limited. A key mechanism involved in the progression of diabetic cardiomyopathy is dysregulation of cardiac energy metabolism. The aim of this study was to determine if increasing the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD; encoded by Acadm), a key regulator of fatty acid oxidation, could improve the function of the diabetic heart. Male mice were administered streptozotocin to induce diabetes, which led to diastolic dysfunction 8 weeks post-injection. Mice then received cardiac-selective adeno-associated viral vectors encoding MCAD (rAAV6:MCAD) or control AAV and were followed for 8 weeks. In the non-diabetic heart, rAAV6:MCAD increased MCAD expression (mRNA and protein) and increased Acadl and Acadvl, but an increase in MCAD enzyme activity was not detectable. rAAV6:MCAD delivery in the diabetic heart increased MCAD mRNA expression but did not significantly increase protein, activity, or improve diabetes-induced cardiac pathology or molecular metabolic and lipid markers. The uptake of AAV viral vectors was reduced in the diabetic versus non-diabetic heart, which may have implications for the translation of AAV therapies into the clinic. KEY MESSAGES: The effects of increasing MCAD in the diabetic heart are unknown. Delivery of rAAV6:MCAD increased MCAD mRNA and protein, but not enzyme activity, in the non-diabetic heart. Independent of MCAD enzyme activity, rAAV6:MCAD increased Acadl and Acadvl in the non-diabetic heart. Increasing MCAD cardiac gene expression alone was not sufficient to protect against diabetes-induced cardiac pathology. AAV transduction efficiency was reduced in the diabetic heart, which has clinical implications.

Chinese herbal medicine and active ingredients for diabetic cardiomyopathy: molecular mechanisms regulating endoplasmic reticulum stress.

Background: Diabetic cardiomyopathy (DCM) is one of the serious microvascular complications of diabetes mellitus. It is often associated with clinical manifestations such as arrhythmias and heart failure, and significantly reduces the quality of life and years of survival of patients. Endoplasmic reticulum stress (ERS) is the removal of unfolded and misfolded proteins and is an important mechanism for the maintenance of cellular homeostasis. ERS plays an important role in the pathogenesis of DCM by causing cardiomyocyte apoptosis, insulin resistance, calcium imbalance, myocardial hypertrophy and fibrosis. Targeting ERS is a new direction in the treatment of DCM. A large number of studies have shown that Chinese herbal medicine and active ingredients can significantly improve the clinical outcome of DCM patients through intervention in ERS and effects on myocardial structure and function, which has become one of the hot research directions. Purpose: The aim of this review is to elucidate and summarize the roles and mechanisms of Chinese herbal medicine and active ingredients that have the potential to modulate endoplasmic reticulum stress, thereby contributing to better management of DCM. Methods: Databases such as PubMed, Web of Science, China National Knowledge Internet, and Wanfang Data Knowledge Service Platform were used to search, analyze, and collect literature, in order to review the mechanisms by which phytochemicals inhibit the progression of DCM by targeting the ERS and its key signaling pathways. Keywords used included "diabetic cardiomyopathy" and "endoplasmic reticulum stress." Results: This review found that Chinese herbs and their active ingredients can regulate ERS through IRE1, ATF6, and PERK pathways to reduce cardiomyocyte apoptosis, ameliorate myocardial fibrosis, and attenuate myocardial hypertrophy for the treatment of DCM. Conclusion: A comprehensive source of information on potential ERS inhibitors is provided in this review. The analysis of the literature suggests that Chinese herbal medicine and its active ingredients can be used as potential drug candidates for the treatment of DCM. In short, we cannot ignore the role of traditional Chinese medicine in regulating ERS and treating DCM, and look forward to more research and new drugs to come.

Compromised diabetic heart function is not affected by miR-378a upregulation upon hyperglycemia

BackgroundCardiac-abundant microRNA-378a (miR-378a) is associated with postnatal repression of insulin–like growth factor 1 receptor (IGF-1R) controlling physiological hypertrophy and survival pathways. IGF-1/IGF-1R axis has been proposed as a therapeutic candidate against the pathophysiological progress of diabetic cardiomyopathy (DCM). We ask whether hyperglycemia-driven changes in miR-378a expression could mediate DCM progression.MethodsDiabetes mellitus was induced by streptozotocin (STZ) (55 mg/kg i.p. for 5 days) in male C57BL/6 wild type (miR-378a+/+) and miR-378a knockout (miR-378a−/−) mice. As a parallel human model, we harnessed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM miR378a+/+ vs. hiPSC-CM miR378a−/−) subjected to high glucose (HG) treatment.ResultsWe reported miR-378a upregulation in cardiac diabetic milieu arising upon STZ administration to wild-type mice and in HG-treated hiPSC-CMs. Pro-hypertrophic IGF-1R/ERK1/2 pathway and hypertrophic marker expression were activated in miR-378a deficiency and upon STZ/HG treatment of miR-378a+/+ specimens in vivo and in vitro suggesting miR-378a-independent hyperglycemia-promoted hypertrophy. A synergistic upregulation of IGF-1R signaling in diabetic conditions was detected in miR-378a−/− hiPSC-CMs, but not in miR-378a−/− hearts that showed attenuation of this pathway, pointing to the involvement of compensatory mechanisms in the absence of miR-378a. Although STZ administration did not cause pro-inflammatory or pro-fibrotic effects that were detected in miR-378a−/− mice, the compromised diabetic heart function observed in vivo by high-resolution ultrasound imaging upon STZ treatment was not affected by miR-378a presence.ConclusionsOverall, data underline the role of miR-378a in maintaining basal cardiac structural integrity while pointing to miR-378a-independent hyperglycemia-driven cardiac hypertrophy and associated dysfunction.