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Pubblicazioni recenti - diabetic cardiomyopathy
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HDAC1 Promotes Myocardial Fibrosis in Diabetic Cardiomyopathy by Inhibiting BMP-7 Transcription Through Histone Deacetylation.
Exp Clin Endocrinol Diabetes2022 Jun;():. doi: 10.1055/a-1780-8768.
Ouyang Chun, Huang Lei, Ye Xiaoqiang, Ren Mingming, Han Zhen,
Abstract
OBJECTIVE:
Diabetic cardiomyopathy (DCM) constitutes a primary cause of mortality in diabetic patients. Histone deacetylase (HDAC) inhibition can alleviate diabetes-associated myocardial injury. This study investigated the mechanism of HDAC1 on myocardial fibrosis (MF) in DCM.
METHODS:
A murine model of DCM was established by a high-fat diet and streptozotocin injection. The bodyweight, blood glucose, serum insulin, and cardiac function of mice were analyzed. Lentivirus-packaged sh-HDAC1 was injected into DCM mice and high glucose (HG)-induced cardiac fibroblasts (CFs). The pathological structure of the myocardium and the level of myocardial fibrosis were observed by histological staining. HDAC1 expression in mouse myocardial tissues and CFs was determined. Collagen I, collagen III, alpha-smooth muscle actin (?-SMA), and vimentin levels in CFs were detected, and CF proliferation was tested. HDAC activity and histone acetylation levels in tissues and cells were measured. Bone morphogenetic protein-7 (BMP-7) expression in myocardial tissues and CFs was determined. Functional rescue experiments were conducted to confirm the effects of histone acetylation and BMP-7 on myocardial fibrosis.
RESULTS:
DCM mice showed decreased bodyweight, elevated blood glucose and serum insulin, and cardiac dysfunction. Elevated HDAC1 and reduced BMP-7 expressions were detected in DCM mice and HG-induced CFs. HDAC1 repressed BMP-7 transcription through deacetylation. HDAC1 silencing alleviated MF, reduced CF proliferation and decreased collagen I, -III, ?-SMA, and vimentin levels. However, reducing histone acetylation level or BMP-7 downregulation reversed the effects of HDAC1 silencing on CF fibrosis.
CONCLUSION:
HDAC1 repressed BMP-7 transcription by enhancing histone deacetylation, thereby promoting MF and aggravating DCM.
Thieme. All rights reserved.
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Loss of Lipocalin 10 Exacerbates Diabetes-Induced Cardiomyopathy Disruption of Nr4a1-Mediated Anti-Inflammatory Response in Macrophages.
Front Immunol2022 ;13():930397. doi: 10.3389/fimmu.2022.930397.
Li Qianqian, Li Yutian, Huang Wei, Wang Xiaohong, Liu Zhenling, Chen Jing, Fan Yanbo, Peng Tianqing, Sadayappan Sakthivel, Wang Yigang, Fan Guo-Chang,
Abstract
Metabolic disorders (i.e., hyperglycemia, hyperlipidemia, and hyperinsulinemia) cause increased secretion of inflammatory cytokines/chemokines, leading to gradual loss of cardiac resident macrophage population and increased accumulation of inflammatory monocytes/macrophages in the heart. Such self-perpetuating effect may contribute to the development of cardiomyopathy during diabetes. Recent meta-analysis data reveal that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue of patients with heart failure but is increased in the blood of septic patients. However, the functional role of Lcn10 in cardiac inflammation triggered by metabolic disorders has never been investigated. In this study, we demonstrate that the expression of Lcn10 in macrophages was significantly decreased under multiple metabolic stress conditions. Furthermore, Lcn10-null macrophages exhibited pro-inflammatory phenotype in response to inflammation stimuli. Next, using a global Lcn10-knockout (KO) mouse model to induce type-2 diabetes (T2D), we observed that loss of Lcn10 promoted more pro-inflammatory macrophage infiltration into the heart, compared to controls, leading to aggravated insulin resistance and impaired cardiac function. Similarly, adoptive transfer of Lcn10-KO bone marrow cells into X-ray irradiated mice displayed higher ratio of pro-/anti-inflammatory macrophages in the heart and worsened cardiac function than those mice received wild-type (WT) bone marrows upon T2D conditions. Mechanistically, RNA-sequencing analysis showed that Nr4a1, a nuclear receptor known to have potent anti-inflammatory effects, is involved in Lcn10-mediated macrophage activation. Indeed, we found that nuclear translocation of Nr4a1 was disrupted in Lcn10-KO macrophages upon stimulation with LPS + IFN?. Accordingly, treatment with Cytosporone B (CsnB), an agonist of Nr4a1, attenuated the pro-inflammatory response in Lcn10-null macrophages and partially improved cardiac function in Lcn10-KO diabetic mice. Together, these findings indicate that loss of Lcn10 skews macrophage polarization to pro-inflammatory phenotype and aggravates cardiac dysfunction during type-2 diabetes through the disruption of Nr4a1-mediated anti-inflammatory signaling pathway in macrophages. Therefore, reduction of Lcn10 expression observed in diabetic macrophages may be responsible for the pathogenesis of diabetes-induced cardiac dysfunction. It suggests that Lcn10 might be a potential therapeutic factor for diabetic heart failure.
Copyright © 2022 Li, Li, Huang, Wang, Liu, Chen, Fan, Peng, Sadayappan, Wang and Fan.
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Cardioprotection by Citrus grandis (L.) Peel Ethanolic Extract in Alloxan-Induced Cardiotoxicity in Diabetic Rats.
Biomed Res Int2022 ;2022():2807337. doi: 10.1155/2022/2807337.
Najar Imtiyaz Ahmed, Bhat Moomin Hussain, Qadrie Zulfqar Lateif, Amaldoss Maria John Newton, Kushwah Ajay Singh, Singh Thakur Gurjeet, Kabra Atul, Khan Nadeem, Kumar Manish,
Abstract
Diabetic cardiomyopathy (DCM) pathogenesis is multifarious, and there are insufficient therapeutic options to treat DCM. The present research explored the effects of Citrus grandis peel ethanolic extract (CGPE) in alloxan-induced DCM in rats. Diabetes was triggered by intraperitoneal (i.p.) injection of alloxan (150?mg/kg) in Wistar rats (200-250?g). CGPE (100, 200, and 400?mg/kg) or glibenclamide (Glib, 10?mg/kg) were administered orally for 2 weeks. After the treatment schedule, prooxidants (thiobarbituric acid reactive substances), antioxidants (glutathione, catalase, and superoxide dismutase), and inflammatory markers (tumor necrosis factor-) were determined in cardiac tissues. Biomarkers of cell death, viz., lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) activity, glucose levels, total cholesterol (TC), and high-density lipoproteins (HDL), were assessed in the blood. Rats administered with alloxan showed a consistent increase in blood glucose level (days 7 and 14) that was lowered considerably (
Copyright © 2022 Imtiyaz Ahmed Najar et al.
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Corrigendum: Lactate and Myocardiac Energy Metabolism.
Front Physiol2022 ;13():947253. doi: 10.3389/fphys.2022.947253.
Dong Shuohui, Qian Linhui, Cheng Zhiqiang, Chen Chang, Wang Kexin, Hu Sanyuan, Zhang Xiang, Wu Tongzhi,
Abstract
[This corrects the article DOI: 10.3389/fphys.2021.715081.].
Copyright © 2022 Dong, Qian, Cheng, Chen, Wang, Hu, Zhang and Wu.
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?-Lapachone, an NQO1 activator, alleviates diabetic cardiomyopathy by regulating antioxidant ability and mitochondrial function.
Phytomedicine2022 Jun;104():154255. doi: S0944-7113(22)00334-8.
Wu Pei-Yu, Lai Shin-Yu, Su Yi-Ting, Yang Kai-Chien, Chau Yat-Pang, Don Ming-Jaw, Lu Kai-Hsi, Shy Horng-Tzer, Lai Shu-Mei, Kung Hsiu-Ni,
Abstract
BACKGROUND:
Diabetic cardiomyopathy (DC) is one of the major lethal complications in patients with diabetes mellitus (DM); however, no specific strategy for preventing or treating DC has been identified.
PURPOSE:
This study aimed to investigate the effects of ?-lapachone (Lap), a natural compound that increases antioxidant activity in various tissues, on DC and explore the underlying mechanisms.
STUDY DESIGN AND METHODS:
As an in vivo model, C57BL/6 mice were fed with the high-fat diet (HF) for 10 weeks to induce type 2 DM. Mice were fed Lap with the HF or after 5 weeks of HF treatment to investigate the protective effects of Lap against DC.
RESULTS:
In the two in vivo models, Lap decreased heart weight, increased heart function, reduced oxidative stress, and elevated mitochondrial content under the HF. In the in vitro model, palmitic acid (PA) was used to mimic the effects of an HF on the differentiated-cardiomyoblast cell line H9c2. The results demonstrated that Lap reduced PA-induced ROS production by increasing the expression of antioxidant regulators and enzymes, inhibiting inflammation, increasing mitochondrial activity, and thus reducing cell damage. Via the use of specific inhibitors and siRNA, the protective effects of Lap were determined to be mediated mainly by NQO1, Sirt1 and mitochondrial activity.
CONCLUSION:
Heart damage in DM is usually caused by excessive oxidative stress. This study showed that Lap can protect the heart from DC by upregulating antioxidant ability and mitochondrial activity in cardiomyocytes. Lap has the potential to serve as a novel therapeutic agent for both the prevention and treatment of DC.
Copyright © 2022 Elsevier GmbH. All rights reserved.
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Secretion of miRNA-326-3p by senescent adipose exacerbates myocardial metabolism in diabetic mice.
J Transl Med2022 Jun;20(1):278. doi: 10.1186/s12967-022-03484-7.
Lin Hao, Chen Xiaonan, Pan Jianan, Ke Jiahan, Zhang Alian, Liu Yangyang, Wang Changqian, Chang Alex Chia Yu, Gu Jun,
Abstract
BACKGROUND:
Adipose tissue homeostasis is at the heart of many metabolic syndromes such as diabetes. Previously it has been demonstrated that adipose tissues from diabetic patients are senescent but whether this contributes to diabetic cardiomyopathy (DCM) remains to be elucidated.
METHODS:
The streptozotocin (STZ) type 1 diabetic mice were established as animal model, and adult mouse ventricular myocytes (AMVMs) isolated by langendorff perfusion as well as neonatal mouse ventricular myocytes (NMVMs) were used as cell models. Senescent associated ? galactosidase (SA-?-gal) staining and RT-qPCR were used to identify the presence of adipose senescence in diabetic adipose tissue. Senescent adipose were removed either by surgery or by senolytic treatment. Large extracellular vesicles (LEVs) derived from adipose tissue and circulation were separated by ultracentrifugation. Cardiac systolic and diastolic function was evaluated through cardiac ultrasound. Cardiomyocytes contraction function was evaluated by the Ionoptix HTS system and live cell imaging, mitochondrial morphology and functions were evaluated by transmission electron microscope, live cell fluorescent probe and seahorse analysis. RNA-seq for AMVMs and miRNA-seq for LEVs were performed, and bioinformatic analysis combined with RT-qPCR and Western blot were used to elucidate underlying mechanism that senescent adipose derives LEVs exacerbates myocardial metabolism.
RESULTS:
SA-?-gal staining and RT-qPCR identified the presence of adipose tissue senescence in STZ mice. Through surgical as well as pharmacological means we show that senescent adipose tissue participates in the pathogenesis of DCM in STZ mice by exacerbates myocardial metabolism through secretion of LEVs. Specifically, expression of miRNA-326-3p was up-regulated in LEVs isolated from senescent adipose tissue, circulation, and cardiomyocytes of STZ mice. Up-regulation of miRNA-326-3p coincided with myocardial transcriptomic changes in metabolism. Functionally, we demonstrate that miRNA-326-3p inhibited the expression of Rictor and resulted in impaired mitochondrial and contractile function in cardiomyocytes.
CONCLUSION:
We demonstrate for the first time that senescent adipose derived LEVs exacerbates myocardial metabolism through up-regulated miRNA-326-3p which inhibits Rictor in cardiomyocytes. Furthermore, reducing senescence burden in adipose tissue is capable of relieving myocardial metabolism disorder in diabetes mellitus.
© 2022. The Author(s).
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Polydatin attenuates chronic alcohol consumption-induced cardiomyopathy through a SIRT6-dependent mechanism.
Food Funct2022 Jun;():. doi: 10.1039/d2fo00966h.
Yu Li-Ming, Dong Xue, Li Ning, Jiang Hui, Zhao Ji-Kai, Xu Yin-Li, Xu Deng-Yue, Xue Xiao-Dong, Zhou Zi-Jun, Huang Yu-Ting, Zhao Qiu-Sheng, Wang Zhi-Shang, Yin Zong-Tao, Wang Hui-Shan,
Abstract
Polydatin has attracted much attention as a potential cardioprotective agent against ischemic heart disease and diabetic cardiomyopathy. However, the effect and mechanism of polydatin supplementation on alcoholic cardiomyopathy (ACM) are still unknown. This study aimed to determine the therapeutic effect of polydatin against ACM and to explore the molecular mechanisms with a focus on SIRT6-AMP-activated protein kinase (AMPK) signaling and mitochondrial function. The ACM model was established by feeding C57/BL6 mice with an ethanol Lieber-DeCarli diet for 12 weeks. The mice received polydatin (20 mg kg) or vehicle treatment. We showed that polydatin treatment not only improved cardiac function but also reduced myocardial fibrosis and dynamin-related protein 1 (Drp-1)-mediated mitochondrial fission, and enhanced PTEN-induced putative kinase 1 (PINK1)-Parkin-dependent mitophagy in alcohol-treated myocardium. Importantly, these beneficial effects were mimicked by SIRT6 overexpression but abolished by the infection of recombinant serotype 9 adeno-associated virus (AAV9) carrying SIRT6-specific small hairpin RNA. Mechanistically, alcohol consumption induced a gradual decrease in the myocardial SIRT6 level, while polydatin effectively activated SIRT6-AMPK signaling and modulated mitochondrial dynamics and mitophagy, thus reducing oxidative stress damage and preserving mitochondrial function. In summary, these data present new information regarding the therapeutic actions of polydatin, suggesting that the activation of SIRT6 signaling may represent a new approach for tackling ACM-related cardiac dysfunction.
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LncRNA MALAT1 Regulates USP22 Expression Through EZH2-Mediated H3K27me3 Modification to Accentuate Sepsis-Induced Myocardial Dysfunction.
Cardiovasc Toxicol2022 Jun;():. doi: 10.1007/s12012-022-09758-2.
Xu Hong, Ye Wei, Shi Baochang,
Abstract
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA), has been confirmed to recruit enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) to regulate cardiomyocyte apoptosis in diabetic cardiomyopathy. However, whether the similar regulatory axis exists in sepsis-induced myocardial dysfunction (SIMD) has not been clearly established. The current study sought to define the mechanism governing MALAT1-mediated EZH2 in SIMD. MALAT1 was significantly upregulated in lipopolysaccharide-induced cardiomyocytes. Depletion of MALAT1 by caudal vein injection of small interfering RNA targeting MALAT1 alleviated myocardial injury in SIMD rats, restored cardiac function, reduced oxidative stress production and fibrosis, and inhibited inflammatory factors and apoptosis in myocardial tissues. Moreover, MALAT1 bound to EZH2 and promoted EZH2 activity in the nucleus of cardiomyocytes. EZH2 repressed ubiquitin-specific peptidase 22 (USP22) expression through H3K27me3 modification. EZH2 elevation aggravated the cardiac injury in SIMD rats, while USP22 upregulation inhibited the effect of EZH2, which reduced the cardiac injury in SIMD rats. Taken together, MALAT1 decreased USP22 expression by interacting with EZH2, thereby worsening SIMD, highlighting an attractive therapeutic strategy for SIMD.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Verification of the folkloric and anecdotal antidiabetic effects of Hypoxis hemerocallidea (Fisch., C.A. Mey. & Avé-Lall) and isolated, ?-sitosterol using early-stage type II spontaneous diabetic mutant BKS-Lepr mice.
BMC Complement Med Ther2022 Jun;22(1):163. doi: 10.1186/s12906-022-03640-y.
Mkolo N M, Olaokun O O, King P H, Janse van Rensburg I, Eloff J N, Naidoo V,
Abstract
BACKGROUND:
Previous studies in our laboratory in ex vivo assays have demonstrated H. hemerocallidea extract as potential antidiabetic agent through increased insulin release from pancreatic beta cells. Thus, for this study the early stage type II spontaneous diabetic mutant mice model was used to evaluate and determine the degree of the antidiabetic efficacy of H. hemerocallidea.
METHODS:
Eight-weeks-old type II spontaneous pre-diabetic mutant BKS-Leprdb mice were fed with feed supplemented with either H. hemerocallidea extract, isolated compound (?-sitosterol) or chlorpropamide (positive control) for 4?weeks. The haematological parameters, clinical chemistry, glucose tolerance, feed intake, faecal output and body weights were measured.
RESULTS:
The blood glucose concentrations of all the animals treated with plant extract, ?-sitosterol compound and non-treated pre-diabetic animals did not return to baseline levels. Only the ?-sitosterol treatment and positive control groups resulted in a respective small decrease of 5.8 and 5.2% in the mouse weights over the study period, with no significant changes (p?>?0.05) in food intake. However, there was a general trend for decrease in faecal output for all the groups. Albumin, triglycerides, and total cholesterol levels in ?-sitosterol and chlorpropamide-treated animals were lower, relative to untreated-animals. Animals fed with plant extract showed large amounts of internal fat. There were no significant changes (p?>?0.05) in total serum protein, globulin, alanine aminotransferase, alkaline phosphatase, urea nitrogen and creatinine attributed to administration of treatments. In all groups, some animals showed lesions associated with cardiac puncture. Few animals except animals treated with plant extract, showed presence of a left-ventricular hypertrophic cardiomyopathy. The liver and kidneys for all groups appeared macroscopically normal and the thymuses were small (±2?mg). There were pathological signs in some of the animals particularly in myocardial fibres, renal tubular, glomerular, hepatocyte granularity and pancreas islets. However, there was no significance trend between the groups.
CONCLUSION:
Based on the results, none of the treatments could be considered highly effective for the management of type II pre-diabetes as sole therapeutic intervention.
© 2022. The Author(s).
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Myocardial fibrosis in type 2 diabetes is associated with functional and metabolomic parameters.
Int J Cardiol2022 Jun;():. doi: S0167-5273(22)00948-2.
Dennis Mark, Howpage Sashie, McGill Margaret, Dutta Shashwati, Koay Yen, Lal Lisa Nguyen, Lal Sean, Wu Ted, Ugander Martin, Wang Alexandra, Munoz Phillip A, Wong Jencia, Constantino Maria I, O'Sullivan John, Twigg Stephen M, Puranik Rajesh,
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Hydroxyurea protects against diabetic cardiomyopathy by inhibiting inflammation and apoptosis.
Biomed Pharmacother2022 Jun;153():113291. doi: S0753-3322(22)00680-1.
Zhou Yu, Lu Qiulun,
Abstract
Hydroxyurea (HU), a small molecule with various biological properties, was used in myeloproliferative, tumorous, and non-hematological diseases. However, whether HU plays a role in diabetic cardiomyopathy (DCM) remains unclear. Our study aimed to investigated whether HU could ameliorate DCM or not. Induction of type 1 diabetes mellitus (T1DM) in C57BL/6 J mice was achieved by intraperitoneal injection of streptozotocin (STZ). Mice in control and diabetic groups were treated with HU (20 mg/kg) in drinking water for 16 weeks. Our data showed that diabetic mice had significantly increased FBG level and decreased body weight, along with abnormal diastolic function and myocardial fibrosis. Inflammatory factors including TNF-?, IL-1?, IL-6, ICAM, VCAM, and apoptosis-related proteins including caspase-3 and BAX were significantly up-regulated in heart tissues. HU treatment remarkably improved these changes. Similarly, application of HU (5 µM) significantly improves the survival rate of high glucose (HG)-treated H9C2 cells. Thus, HU rescued the cardiomyocytes via inhibition of apoptosis and inflammation in DCM.
Copyright © 2022. Published by Elsevier Masson SAS.
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Integrative pharmacology reveals the mechanisms of Erzhi Pill, a traditional Chinese formulation, against diabetic cardiomyopathy.
J Ethnopharmacol2022 Jun;296():115474. doi: S0378-8741(22)00513-X.
Peng Mingming, Xia Tianyi, Zhong Yanmei, Zhao Mantong, Yue Yimin, Liang Lanyuan, Zhong Renxing, Zhang Han, Li Chuanqiu, Cao Xia, Yang Mengru, Wang Yi, Shu Zunpeng,
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Erzhi Pill (EZP) is a traditional Chinese prescription that has marked effects in treating type 2 diabetes mellitus and diabetic nephropathy. However, its underlying pharmacological mechanisms in the treatment of diabetic cardiomyopathy (DCM), remain to be elucidated.
AIM OF THE STUDY:
This study aimed to apply an integrative pharmacological strategy to systematically evaluate the pharmacological effects and molecular mechanisms of EZP, and provide a solid theoretical basis for the clinical application of EZP in the treatment of DCM.
MATERIALS AND METHODS:
In this study, the potential targets and key pathways of EZP were predicted and validated using network pharmacology and molecular docking, respectively. Changes in cardiac metabolites and major metabolic pathways in rat heart samples were examined using H-nuclear magnetic resonance (NMR) metabolomics. Finally, biochemical analysis was conducted to detect the protein expression levels of key pathways.
RESULTS:
We found that EZP decreased fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) levels, increased high-density lipoprotein (HDL) levels in the serum, and alleviated the morphological abnormalities of the heart tissue in diabetic rats. Furthermore, EZP effectively restored superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), caspase-3, caspase-8, and caspase-9 activity levels, as well as the levels of reactive oxygen species (ROS), malondialdehyde (MDA), B-cell lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) in the heart tissue. Network pharmacology prediction results indicated that the mechanism of EZP in treating DCM was closely related to apoptosis, oxidative stress, and the HIF-1, PI3K-Akt, and FoxO signaling pathways. In addition, H-NMR metabolomics confirmed that EZP primarily regulated both energy metabolism and amino acid metabolism, including the tricarboxylic acid (TCA) cycle, ketone bodies metabolism, glutamine and glutamate metabolism, glycine metabolism, and purine metabolism. Finally, immunohistochemistry results indicated that EZP reduced the expression levels of p-AMPK, p-PI3K, p-Akt, and p-FoxO3a proteins, in the heart tissue of DCM rats.
CONCLUSION:
The results confirmed that the overall therapeutic effect of EZP in the DCM rat model is exerted via inhibition of oxidative stress and apoptosis, alongside the regulation of energy metabolism and amino acid metabolism, as well as the AMPK and PI3K/Akt/FoxO3a signaling pathways. This study provides an experimental basis for the use of EZP in DCM treatment.
Copyright © 2022 Elsevier B.V. All rights reserved.
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Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: Evidence in Human Cardiomyocytes.
Front Mol Biosci2022 ;9():879522. doi: 10.3389/fmolb.2022.879522.
Giannattasio Silvia, Citarella Anna, Trocchianesi Sofia, Filardi Tiziana, Morano Susanna, Lenzi Andrea, Ferretti Elisabetta, Crescioli Clara,
Abstract
The antidiabetic sodium-glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin efficiently reduces heart failure (HF) hospitalization and cardiovascular death in type 2 diabetes (T2D). Empagliflozin-cardioprotection likely includes anti-inflammatory effects, regardless glucose lowering, but the underlying mechanisms remain unclear. Inflammation is a primary event in diabetic cardiomyopathy (DCM) and HF development. The interferon (IFN)?-induced 10-kDa protein (IP-10/CXCL10), a T helper 1 (Th1)-type chemokine, promotes cardiac inflammation, fibrosis, and diseases, including DCM, ideally representing a therapeutic target. This preliminary study aims to explore whether empagliflozin directly affects Th1-challenged human cardiomyocytes, in terms of CXCL10 targeting. To this purpose, empagliflozin dose-response curves were performed in cultured human cardiomyocytes maintained within a Th1-dominant inflammatory microenvironment (IFN?/TNF?), and CXCL10 release with the intracellular IFN?-dependent signaling pathway (Stat-1) was investigated. To verify possible drug-cell-target specificity, the same assays were run in human skeletal muscle cells. Empagliflozin dose dependently inhibited CXCL10 secretion (IC50 = 76,14 × 10-9 M) in association with Stat-1 pathway impairment only in Th1-induced human cardiomyocytes, suggesting drug-selective cell-type-targeting. As CXCL10 plays multifaceted functions in cardiac remodeling toward HF and currently there is no effective method to prevent it, these preliminary data might be hypothesis generating to open new scenarios in the translational approach to SGLT2i-dependent cardioprotection.
Copyright © 2022 Giannattasio, Citarella, Trocchianesi, Filardi, Morano, Lenzi, Ferretti and Crescioli.
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Molecular Mechanisms of Hawthorn Extracts in Multiple Organs Disorders in Underlying of Diabetes: A Review.
Int J Endocrinol2022 ;2022():2002768. doi: 10.1155/2022/2002768.
Gheitasi Izadpanah, Savari Feryal, Akbari Ghaidafeh, Mohammadi Jamshid, Fallahzadeh Ali Reza, Sadeghi Hossein,
Abstract
Diabetes mellitus (DM) is one of the most important metabolic disorders associated with chronic hyperglycemia and occurs when the body cannot manage insulin secretion, insulin action, or both. Autoimmune destruction of pancreatic beta cells and insulin resistance are the major pathophysiological factors of types 1 and 2 of DM, respectively. Prolonged hyperglycemia leads to multiple organs dysfunctions, including nephropathy, neuropathy, cardiomyopathy, gastropathy, and micro- and macrovascular disorders. The basis of the metabolic abnormalities in carbohydrate, fat, and protein in diabetes is insufficient action of insulin on various target tissues. Medicinal plants are rich sources of bioactive chemical compounds with therapeutic effects. The beneficial effects of leaves, fruits, and flowers extracts of commonly called hawthorn, belonging to the Rosaceae family, are widely used as hawthorn-derived medicines. Data in this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2021. Based on this review, hawthorn extracts appear both therapeutic and protective effects against diabetic-related complications in various organs through molecular mechanisms, such as decreasing triglyceride, cholesterol, very low density lipoprotein and increasing the antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, total antioxidant capacity, decreasing malondialdehyde level, and attenuating tumor necrosis factor alpha, interleukin 6 and sirtuin 1/AMP-activated protein kinase (AMPK)/nuclear factor kappa B (NF-B) pathway and increasing the phosphorylation of glucose transporter 4, insulin receptor substrate 1, AKT and phosphoinositide 3-kinases, and attenuating blood sugar and regulation of insulin secretion, insulin resistance, and improvement of histopathological changes in pancreatic beta cells. Collectively, hawthorn can be considered as one new target for the research and development of innovative drugs for the prevention or treatment of DM and related problems.
Copyright © 2022 Izadpanah Gheitasi et al.
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Aerobic Exercise Inhibited P2X7 Purinergic Receptors to Improve Cardiac Remodeling in Mice With Type 2 Diabetes.
Front Physiol2022 ;13():828020. doi: 10.3389/fphys.2022.828020.
Wang Ting, Li Jianmin, Li Hui, Zhong Xin, Wang Luya, Zhao Shujue, Liu Xuesheng, Huang Zhouqing, Wang Yonghua,
Abstract
Diabetic cardiomyopathy (DCM), the main complication of diabetes mellitus, presents as cardiac dysfunction by ventricular remodeling. In addition, the inhibition of P2X7 purinergic receptors (P2X7R) alleviates cardiac fibrosis and apoptosis in Type 1 diabetes. However, whether exercise training improves cardiac remodeling by regulating P2X7R remains unknown. Db/db mice spontaneously induced with type 2 diabetes and high-fat diet (HFD) and mice with streptozotocin (STZ)-induced type 2 diabetes mice were treated by 12-week treadmill training. Cardiac functions were observed by two-dimensional echocardiography. Hematoxylin-eosin staining, Sirius red staining and transmission electron microscopy were respectively used to detect cardiac morphology, fibrosis and mitochondria. In addition, real-time polymerase chain reaction and Western Blot were used to detect mRNA and protein levels. Studying the hearts of db/db mice and STZ-induced mice, we found that collagen deposition and the number of disordered cells significantly increased compared with the control group. However, exercise markedly reversed these changes, and the same tendency was observed in the expression of MMP9, COL-I, and TGF-?, which indicated cardiac fibrotic and hypertrophic markers, including ANP and MyHC expression. In addition, the increased Caspase-3 level and the ratio of Bax/Bcl2 were reduced by exercise training, and similar results were observed in the TUNEL test. Notably, the expression of P2X7R was greatly upregulated in the hearts of db/db mice and HFD + STZ-induced DM mice and downregulated by aerobic exercise. Moreover, we indicated that P2X7R knock out significantly reduced the collagen deposition and disordered cells in the DM group. Furthermore, the apoptosis levels and TUNEL analysis were greatly inhibited by exercise or in the P2X7R group in DM. We found significant differences between the P2X7R + DM + EX group and DM + EX group in myocardial tissue apoptosis and fibrosis, in which the former is significantly milder. Moreover, compared with the P2X7R + DM group, the P2X7R + DM + EX group represented a lower level of cardiac fibrosis. The expression levels of TGF-? at the protein level and TGF-? and ANP at the genetic level were evidently decreased in the P2X7R + DM + EX group. Aerobic exercise reversed cardiac remodeling in diabetic mice at least partly through inhibiting P2X7R expression in cardiomyocytes.
Copyright © 2022 Wang, Li, Li, Zhong, Wang, Zhao, Liu, Huang and Wang.
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Combination of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos improves cardiac function of diabetic cardiomyopathy mice by regulating the unfolded protein response signaling pathway.
Phytother Res2022 Jun;():. doi: 10.1002/ptr.7524.
Li Jianping, Xu Meiling, Xing Baotong, Liu Yun, Zhang Qian, Guo Jianming, Duan Jinao,
Abstract
Diabetic cardiomyopathy (DCM) is a unique clinical entity elicited by diabetes independent of other cardiovascular risk factors, of which the pathological mechanisms and treatment strategies remain largely undefined. This study aimed to clarify the role of unfolded protein response (UPR) signaling pathway in the pathogenesis of DCM, and to explore the effect of aqueous extract of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos (DH) on DCM mice. Cardiac function of DCM mice was evaluated by echocardiography, and lipid profile of left ventricular was analyzed by untargeted lipidomics. The results showed that DH significantly improved the diabetic symptoms, cardiac dyslipidemia, and systolic dysfunction of DCM mice. UPR signaling pathway was significantly down-regulated in the left ventricular of DCM mice. DH significantly up-regulated the transcriptions of key transducers in UPR signaling pathway. Conditional knockout of Xbp1 in cardiomyocyte (a key regulator in UPR signaling pathway) eliminated the protective effect of DH on cardiac systolic function of DCM mice, which suggested that UPR signaling pathway, especially the Xbp1, was required for DH protection against DCM. In conclusion, DH improved cardiac function of DCM mice, and this effect was dependent on its regulation of UPR signaling pathway.
© 2022 John Wiley & Sons Ltd.
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Glucose fluctuation promotes cardiomyocyte apoptosis by triggering endoplasmic reticulum (ER) stress signaling pathway and .
Bioengineered2022 05;13(5):13739-13751. doi: 10.1080/21655979.2022.2080413.
Wu Li-Da, Liu Ying, Li Feng, Chen Jia-Yi, Zhang Jie, Qian Ling-Ling, Wang Ru-Xing,
Abstract
Glucose fluctuation is more harmful than sustained hyperglycemia, but the effect on cardiomyocyte apoptosis have not yet been clarified. In this study, we aim to identify the effect of glucose fluctuation on cardiomyocyte apoptosis and explore the underlying mechanism. Sprague-Dawley rats were intraperitoneally injected with streptozotocin (STZ) and divided into three groups: controlled diabetic group (C-STZ); uncontrolled diabetic group (U-STZ) and glucose fluctuated diabetic group (GF-STZ). After twelve weeks, echocardiography, Hematoxylin-eosin (HE) staining, and Masson staining were adopted to assess the cardiac function and pathological changes. TUNEL staining was used to detect apoptotic cells. Expressions of apoptosis-related proteins and key molecules in the endoplasmic reticulum (ER) stress pathway were determined via western blots. Further, primary cardiomyocytes incubated in different glucose conditions were treated with the inhibitor of ER stress to explore the causative role of ER stress in glucose fluctuation-induced cardiomyocyte apoptosis. , we demonstrated that glucose fluctuation promoted cardiomyocyte apoptosis, and were more harmful to cardiomyocytes than sustained hyperglycemia. Moreover, glucose fluctuation significantly triggered ER stress signaling pathway. , primary cardiomyocyte apoptosis induced by glucose fluctuation and the activation of ER stress were significantly attenuated by 4-PBA, which is an ER stress inhibitor. Above all, glucose fluctuation can promote cardiomyocyte apoptosis through triggering the ER stress signaling pathway in diabetic rats and in primary cardiomyocytes.
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Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial.
Sci Transl Med2022 Jun;14(649):eabl8503. doi: 10.1126/scitranslmed.abl8503.
Pofi Riccardo, Giannetta Elisa, Feola Tiziana, Galea Nicola, Barbagallo Federica, Campolo Federica, Badagliacca Roberto, Barbano Biagio, Ciolina Federica, Defeudis Giuseppe, Filardi Tiziana, Sesti Franz, Minnetti Marianna, Vizza Carmine D, Pasqualetti Patrizio, Caboni Pierluigi, Carbone Iacopo, Francone Marco, Catalano Carlo, Pozzilli Paolo, Lenzi Andrea, Venneri Mary Anna, Gianfrilli Daniele, Isidori Andrea M,
Abstract
Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c
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Hydrogen sulphide: Diabetic cardiomyopathy as the paradigm of its pleiotropic function.
Eur J Clin Invest -
Emerging Role of Epitranscriptomics in Diabetes Mellitus and Its Complications.
Front Endocrinol (Lausanne)2022 ;13():907060. doi: 10.3389/fendo.2022.907060.
Geng Xinqian, Li Zheng, Yang Ying,
Abstract
Diabetes mellitus (DM) and its related complications are among the leading causes of disability and mortality worldwide. Substantial studies have explored epigenetic regulation that is involved in the modifications of DNA and proteins, but RNA modifications in diabetes are still poorly investigated. In recent years, posttranscriptional epigenetic modification of RNA (the so-called 'epitranscriptome') has emerged as an interesting field of research. Numerous modifications, mainly -methyladenosine (mA), have been identified in nearly all types of RNAs and have been demonstrated to have an indispensable effect in a variety of human diseases, such as cancer, obesity, and diabetes. Therefore, it is particularly important to understand the molecular basis of RNA modifications, which might provide a new perspective for the pathogenesis of diabetes mellitus and the discovery of new therapeutic targets. In this review, we aim to summarize the recent progress in the epitranscriptomics involved in diabetes and diabetes-related complications. We hope to provide some insights for enriching the understanding of the epitranscriptomic regulatory mechanisms of this disease as well as the development of novel therapeutic targets for future clinical benefit.
Copyright © 2022 Geng, Li and Yang.
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