Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways

Acta Pharmaceutica Sinica B, Journal Year: 2021, Volume and Issue: 12(2), P. 708 - 722

Published: Oct. 19, 2021

Herein, we define the role of ferroptosis in pathogenesis diabetic cardiomyopathy (DCM) by examining expression key regulators mice with DCM and a new ex vivo model. Advanced glycation end-products (AGEs), an important pathogenic factor DCM, were found to induce engineered cardiac tissues (ECTs), as reflected through increased levels Ptgs2 lipid peroxides decreased ferritin SLC7A11 levels. Typical morphological changes cardiomyocytes observed using transmission electron microscopy. Inhibition ferrostatin-1 deferoxamine prevented AGE-induced ECT remodeling dysfunction. Ferroptosis was also evidenced heart type 2 DCM. liproxstatin-1 development diastolic dysfunction at 3 months after onset diabetes. Nuclear erythroid 2-related (NRF2) activated sulforaphane inhibited cell both AGE-treated ECTs hearts upregulating The protective effect on AMP-activated protein kinase (AMPK)-dependent. These findings suggest that plays essential DCM; prevents associated via AMPK-mediated NRF2 activation. This suggests feasible therapeutic approach clinically prevent

Language: Английский

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FGF21–Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity

Circulation, Journal Year: 2022, Volume and Issue: 146(20), P. 1537 - 1557

Published: Oct. 19, 2022

Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as exercise responsive factor. This study aims investigate whether signaling mediates the of DCM, and if so, elucidate underlying The global or hepatocyte-specific knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) their wild-type littermates were subjected high-fat diet feeding injection streptozotocin induce followed by 6-week intervention assessment cardiac functions. Cardiac mitochondrial structure function assessed electron microscopy, enzymatic assays, measurements fatty acid oxidation ATP production. Human induced pluripotent stem cell-derived cardiomyocytes used receptor postreceptor pathways conferring protective effects against toxic lipids-induced dysfunction. Treadmill markedly expression significantly attenuated diabetes-induced dysfunction in accompanied reduced damage increased activities enzymes hearts. However, such cardioprotective largely abrogated mice hepatocyte-selective ablation FGF21, cardiomyocyte-specific deletion β-klotho. Mechanistically, enhanced actions deacetylase SIRT3 AMPK-evoked phosphorylation FOXO3, thereby reversing hyperacetylation functional impairments cluster enzymes. prevented oxidative stress induction AMPK/FOXO3/SIRT3 axis human cardiomyocytes. Adeno-associated virus-mediated restoration was sufficient restore responsiveness amelioration DCM. FGF21-SIRT3 DCM preserving integrity represents potential therapeutic target URL: https://www. gov; Unique identifier: NCT03240978.

Language: Английский

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The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: June 30, 2021

Individuals with diabetes mellitus (DM) disclose a higher incidence and poorer prognosis of heart failure (HF) than non-diabetic people, even in the absence other HF risk factors. The adverse impact on likely reflects an underlying "diabetic cardiomyopathy" (DM-CMP), which may by exacerbated left ventricular hypertrophy coronary artery disease (CAD). pathogenesis DM-CMP has been hot topic research since its first description is still under active investigation, as complex interplay among multiple mechanisms play role at systemic, myocardial, cellular/molecular levels. Among these, metabolic abnormalities such lipotoxicity glucotoxicity, mitochondrial damage dysfunction, oxidative stress, abnormal calcium signaling, inflammation, epigenetic factors, others. These disturbances predispose diabetic to extracellular remodeling hypertrophy, thus leading diastolic systolic dysfunction. This Review aims outline major pathophysiological changes myocardial cardiac functional derangement DM-CMP.

Language: Английский

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6-Gingerol Alleviates Ferroptosis and Inflammation of Diabetic Cardiomyopathy via the Nrf2/HO-1 Pathway

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 12

Published: Dec. 31, 2022

Background. Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments consequently increase risk of mortality. Objective. To characterize the therapeutic effect 6-gingerol (6-G) on DCM identify its potential mechanism. Methods. In vivo streptozotocin- (STZ-) induced DM model was established by using a high-fat diet STZ, followed low-dose (25 mg/kg) high-dose (75 6-G intervention. For an in vitro model, H9c2 rat cardiomyoblast cells were stimulated with high glucose ( glucose = 33 mM) palmitic acid (100 μM) then treated μM). Histological echocardiographic analyses used assess cardiac structure function DCM. Western blotting, ELISA, real-time qPCR expression ferroptosis, inflammation, Nrf2/HO-1 pathway-related proteins RNAs. Protein collagen I III assessed immunohistochemistry, kits assay SOD, MDA, iron levels. Results. The results showed that decreased both mouse cell models hypertrophy interstitial fibrosis attenuated treatment resulted improved heart function. inhibited ferroptosis-related protein FACL4 content enhanced anti-ferroptosis-related GPX4. addition, also diminished secretion inflammatory cytokines, including IL-1β, IL-6, TNF-α. activated pathway, antioxidative stress capacity proved increased activity MDA production. Compared vivo, could produce similar effect. Conclusion. These findings suggest protect against mechanism ferroptosis inhibition inflammation reduction via enhancing pathway.

Language: Английский

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Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: June 15, 2022

Diabetes is a chronic metabolic disease that increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) complication of diabetes associated with high mortality, but it not well defined. Nevertheless, generally accepted DCM refers to clinical occurs patients involves ventricular dysfunction, the absence other cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, or valvular disease. However, currently uncertain whether pathogenesis directly attributable dysfunction secondary diabetic microangiopathy. Oxidative stress (OS) considered be key component its pathogenesis. The production reactive oxygen species (ROS) cardiomyocytes vicious circle, resulting further ROS, mitochondrial DNA damage, lipid peroxidation, post-translational modification proteins, inflammation, cardiac hypertrophy fibrosis, ultimately leading cell death dysfunction. ROS have been shown affect various signaling pathways involved development DCM. For instance, OS disorders by affecting regulation PPARα, AMPK/mTOR, SIRT3/FOXO3a. Furthermore, participates inflammation mediated NF-κB pathway, NLRP3 inflammasome, TLR4 pathway. also promotes TGF-β-, Rho-ROCK-, Notch-mediated remodeling, calcium homeostasis, which impairs ATP overproduction. In this review, we summarize link DCM, intention identifying appropriate targets new antioxidant therapies for

Language: Английский

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SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases

Aging and Disease, Journal Year: 2022, Volume and Issue: 13(6), P. 1787 - 1787

Published: Jan. 1, 2022

As an important NAD⁺-dependent enzyme, SIRT6 has received significant attention since its discovery. In view of observations that SIRT6-deficient animals exhibit genomic instability and metabolic disorders undergo early death, long been considered a protein longevity. Recently, growing evidence demonstrated functions as deacetylase, mono-ADP-ribosyltransferase fatty deacylase participates in variety cellular signaling pathways from DNA damage repair the stage to disease progression. this review, we elaborate on specific substrates molecular mechanisms various physiological pathological processes detail, emphasizing links aging (genomic damage, telomere integrity, repair), metabolism (glycolysis, gluconeogenesis, insulin secretion lipid synthesis, lipolysis, thermogenesis), inflammation cardiovascular diseases (atherosclerosis, cardiac hypertrophy, heart failure, ischemia-reperfusion injury). addition, most recent advances regarding modulators (agonists inhibitors) potential therapeutic agents for SIRT6-mediated are reviewed.

Language: Английский

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CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 8, 2023

Abstract In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cell hypertrophy, and fibrosis occurred deficiency ( +/− ) mice, whereas DCM alleviated DICAR-overexpressed Tg mice. At cellular level, found overexpression of inhibited, but knockdown enhanced cardiomyocyte pyroptosis. molecular DICAR-VCP-Med12 degradation could be underlying mechanism DICAR-mediated effects. The synthesized junction part (DICAR-JP) exhibited similar to entire DICAR. addition, expression circulating blood cells plasma from patients lower than health controls, consistent with decreased DICAR-JP may drug candidates for DCM.

Language: Английский

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Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes by Inhibiting Inflammation and Ferroptosis through Activating AMPK Pathway

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(1), P. 858 - 858

Published: Jan. 3, 2023

Diabetic cardiomyopathy (DCM) is a myocardial disease independent of other cardiovascular diseases, such as coronary heart disease, hypertension, etc. Lipotoxicity closely related to DCM. In this study, we investigated the mechanism lipid metabolism disturbance in DCM HL-1 cells. Through bioinformatics and Western blotting analysis, found that canagliflozin (CAN) significantly inhibited expression inflammatory factors cyclooxygenase-2 (COX-2) inducible nitric oxide synthase (iNOS). Ferroptosis mediated by peroxidation. We demonstrated presence ferroptosis cardiomyocytes detecting intracellular Fe2+ content levels reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH), mitochondrial membrane potential (MMP). CAN could regulate indicators ferroptosis. By using specific inhibitors celecoxib (coxib), S-methylisothiourea sulfate (SMT), Ferrostatin-1 (Fer-1), Compound C, further regulated inflammation through AMP-activated protein (AMPK), interacted with Our study indicated attenuated lipotoxicity regulating activating AMPK pathway. This provides new direction some information for treatment

Language: Английский

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Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 31, 2024

Abstract The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate system, macrophages play an essential initial inflammatory that occurs following injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, diverse phenotypes and phenotypic alterations strongly associate with distinct types severity diseases, including coronary heart disease, valvular myocarditis, cardiomyopathy, failure, atherosclerosis aneurysm, which underscores importance investigating macrophage regulatory mechanisms within context specific diseases. Besides, recent strides single-cell sequencing technologies have revealed heterogeneity, cell–cell interactions, downstream therapeutic targets at higher resolution, brings new perspectives into macrophage-mediated potential Remarkably, myocardial fibrosis, prevalent characteristic most cardiac remains formidable clinical challenge, necessitating profound investigation impact on fibrosis In this review, we systematically summarize functional plasticity diseases unprecedented insights introduced by technologies, focus different causes characteristics especially relationship between inflammation (myocardial infarction, pressure overload, dilated diabetic cardiomyopathy aging) vascular injury (atherosclerosis aneurysm). Finally, highlight preclinical/clinical targeting strategies translational implications.

Language: Английский

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Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications

Antioxidants, Journal Year: 2023, Volume and Issue: 12(1), P. 123 - 123

Published: Jan. 4, 2023

The global prevalence of diabetes continues to increase partly due rapid urbanization and an in the aging population. Consequently, this is associated with a parallel diabetic vascular complications which significantly worsen burden diabetes. For these complications, there still unmet need for safe effective alternative/adjuvant therapeutic interventions. There also increasing urge options come from natural products such as plants. Hyperglycemia-induced oxidative stress central development complications. Furthermore, stress-induced inflammation insulin resistance are endothelial damage progression Human animal studies have shown that polyphenols could reduce stress, hyperglycemia, prevent including retinopathy, nephropathy, peripheral neuropathy. Part effects attributed their modulatory effect on endogenous antioxidant systems. This review attempts summarize established systems literature. Moreover, potential strategies harnessing benefits discussed.

Language: Английский

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