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Pubblicazioni recenti - diabetic cardiomyopathy
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Identification and verification of immune-related biomarkers and immune infiltration in diabetic heart failure.
Front Cardiovasc Med2022 ;9():931066. doi: 931066.
Zhong Zuoquan, Zhang Hanlin, Xu Ting, Hao Jinjin, Chen Xing, Sun Shimin, Yang Jinjin, Sun Jing, Lin Hui, Guo Hangyuan,
Abstract
PURPOSE:
Diabetic heart failure (DHF) or cardiomyopathy is a common complication of diabetes; however, the underlying mechanism is not clear. In the present study, the authors searched for differentially expressed genes associated with DHF and the molecular types of immune cells based on bioinformatics.
METHODS:
The RNA expression dataset of DHF was obtained from the NCBI Gene Expression Omnibus (GEO) database. After preprocessing the data, the differentially expressed genes (DEGs) between the DHF group and the non-diabetic heart failure (NHF) group were screened and intersected with immune-related genes (IRGs) in the ImmPort database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID tool. The ssGSEA algorithm was used to evaluate immune infiltration of the heart tissue in each group. In addition, the protein-protein interaction (PPI) network and miRNA-mRNA network were constructed using the STRING online website and Cytoscape program. Finally, validation analysis was performed using animal models.
RESULTS:
Eight immune-related core genes were identified. GO and KEGG showed that core genes were mainly enriched in angiogenesis and cytokine-cytokine receptor interaction. Immune infiltration results showed that activated dendritic cells, central memory CD4 T cells, central memory CD8 T cells, myeloid-derived suppressor cells (MDSCs), neutrophils, and regulatory T cells may be involved in DHF. Neutrophils may play a key role in the pathogenesis of HF in diabetes.
CONCLUSION:
Immune-related core genes and immune infiltrating cells provide a new perspective on the pathogenesis of DHF.
Copyright © 2022 Zhong, Zhang, Xu, Hao, Chen, Sun, Yang, Sun, Lin and Guo.
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Serum Annexin A2 concentrations are increased in patients with diabetic cardiomyopathy and are linked to cardiac dysfunctions.
Diabetes Res Clin Pract2022 Dec;195():110196. doi: 10.1016/j.diabres.2022.110196.
He Qingshan, Zhu Jiaran, Yang Guojun, Liu Xiufei, Li Lu, Wang Yuren, Xiong Xin, Zheng Yi, Zheng Hongting, Qu Hua,
Abstract
BACKGROUND:
Diabetic cardiomyopathy (DbCM) is defined as the existence of abnormal myocardial structure and functions in the absence of other cardiac diseases, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes. Although abundant epidemic evidence demonstrates that diabetes is independently associated with the risk of developing heart failure, DbCM is not normally diagnosed in clinical practices due to its exclusive diagnosis, and no diagnostic biomarker was applied in a clinical test.
METHODS:
To detect the concentrations of serum Annexin A2 in non-diabetic subjects, type 2 diabetic (T2DM) patients with or without DbCM, and analyzed its relationship to parameters of cardiac functions, glucose, lipid metabolism, and renal functions. 266 eligible participants were included and were divided into 3 groups including non-diabetic subjects (NGR), T2DM patients without DbCM (T2DM group), and the DbCM group. Echocardiography, coronary computed tomography angiography, electrocardiogram, blood pressure, thyroid function, and clinical and other biochemical parameters were measured in all participants.
RESULTS:
Serum Annexin A2 concentrations were higher in DbCM (P
CONCLUSIONS:
Circulating Annexin A2 concentrations might be induced in DbCM patients and were negatively associated with cardiac systolic and diastolic functions, which suggested it might be a predictor of early diagnosis in DbCM and might be a potential therapeutic target for DbCM.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
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Normal and excessive muscle sympathetic nerve activity in heart failure: implications for future trials of therapeutic autonomic modulation.
Eur J Heart Fail2022 Dec;():. doi: 10.1002/ejhf.2749.
Badrov Mark B, Keir Daniel A, Tomlinson George, Notarius Catherine F, Millar Philip J, Kimmerly Derek S, Shoemaker J Kevin, Keys Evan, Floras John S,
Abstract
AIMS:
Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls.
METHODS AND RESULTS:
We compared data acquired in 177 conventionally-treated, stable non-diabetic patients in sinus rhythm, aged 18-79?years (149 males; 28 females; LVEF: 25±11% [mean±SD]; range 5-60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; 260 females; aged 18-81?years). In heart failure, MSNA ranged between 7 and 90 bursts·min , proportionate to heart rate (P
CONCLUSION:
Burst frequency and incidence exceeded normative values in only ~53% and ~33% of patients. Such diversity encourages selective deployment of sympatho-modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation.
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Melatonin ameliorates myocardial infarction in obese diabetic individuals: the possible involvement of macrophage apoptotic factors.
J Pineal Res2022 Dec;():. doi: 10.1111/jpi.12847.
Maity Juin, Dey Tiyasa, Banerjee Adrita, Chattopadhyay Aindrila, Das Asish R, Bandyopadhyay Debasish,
Abstract
In recent days, the hike in obesity mediated epidemic across the globe and prevalence of obesity induced cardiovascular disease (CVD) has become one of the chief grounds of morbidity and mortality. This epidemic driven detrimental events in the cardiac tissues starts with the altered distribution and metabolism pattern of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on arterial wall and atherosclerotic plaque generation, followed by vascular spasm and infarction. Subsequently, obesity triggered metabolic malfunction induce free radical generation which may further trigger pro-inflammatory signalling and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) transcriptional factor, thus inducing interferon-gamma (IFN-?), tumour necrosis factor-alpha (TNF-?), and inducible nitric oxide synthase (iNOS). This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby turning the obese diabetic patients prone towards the development of myocardial infarction or stroke in comparison to their non diabetic counterparts. The accelerated oxidative stress and pro-inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals causes progression of athero-thrombotic vascular disease. Being an efficient antioxidative and anti-inflammatory indolamine, melatonin effectively inhibits lipid peroxidation (LPO), pro-inflammatory reactions, thereby resolving free radical induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterol (TC) concentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti-inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity induced acute myocardial infarction (AMI). This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity- diabetes correlation. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Targeting Mitochondrial Calcium Handling to Treat Atrial Fibrillation.
J Am Coll Cardiol2022 Dec;80(23):2220-2223. doi: 10.1016/j.jacc.2022.09.043.
Voigt Niels, Maack Christoph, Pronto Julius Ryan D,
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Enhanced Mitochondrial Calcium Uptake Suppresses Atrial Fibrillation Associated With Metabolic Syndrome.
J Am Coll Cardiol2022 Dec;80(23):2205-2219. doi: 10.1016/j.jacc.2022.09.041.
Fossier Lucile, Panel Mathieu, Butruille Laura, Colombani Sarah, Azria Lan, Woitrain Eloise, Decoin Raphael, Torrente Angelo G, Thireau Jérôme, Lacampagne Alain, Montaigne David, Fauconnier Jérémy,
Abstract
BACKGROUND:
Patients with metabolic syndrome (MetS) have an increased risk of atrial fibrillation (AF). Impaired Ca homeostasis and mitochondrial dysfunction have emerged as an arrhythmogenic substrate in both patients and animal models of MetS. Whether impaired mitochondrial Ca handling underlies AF associated with MetS remains poorly explored.
OBJECTIVES:
The aim of this study was to determine the initial mechanisms related to AF susceptibility and mitochondrial dysfunction encountered in metabolic cardiomyopathy.
METHODS:
A total of 161 mice and 34 patients were studied. Mitochondrial Ca and mitochondrial Ca uniporter complex (MCUC) were investigated in right atrial tissue of patients with (n = 18) or without (n = 16) MetS and of C57Bl/6J mice fed with a high-fat sucrose diet (HFS) for 2 (n = 42) or 12 (n = 39) weeks. Susceptibility to AF was evaluated in isolated sinoatrial tissue and in vivo in mice.
RESULTS:
Increased expression of the MICUs subunits of the MCUC (1.00 ± 0.33 AU vs 1.29 ± 0.23 AU; P = 0.034) was associated with impaired mitochondrial Ca uptake in patients (168.7 ± 31.3 nmol/min/mg vs 127.3 ± 18.4 nmol/min/mg; P = 0.026) and HFS mice (0.10 ± 0.04 ?F/F0 × ms vs 0.06 ± 0.03 ?F/F0 × ms; P = 0.0086, and 0.15 ± 0.07 ?F/F0 × ms vs 0.046 ± 0.03 ?F/F0 × ms; P = 0.0076 in 2- and 12-week HFS mice, respectively). HFS mice elicited a 70% increased susceptibility to AF. The MCUC agonist kaempferol restored MCUC activity in vitro and abolished the occurrence of AF in HFS mice.
CONCLUSIONS:
Impaired MCUC activity and mitochondrial Ca homeostasis from the early stage of metabolic cardiomyopathy in mice lead to AF. Given that similar defects in cardiac mitochondrial Ca handling are present in MetS patients, the modulation of the MCUC activity represents an attractive antiarrhythmic strategy.
Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Genome Editing and Diabetic Cardiomyopathy.
Adv Exp Med Biol2023 ;1396():103-114. doi: 10.1007/978-981-19-5642-3_7.
Kambis Tyler N, Mishra Paras K,
Abstract
Differential gene expression is associated with diabetic cardiomyopathy (DMCM) and culminates in adverse remodeling in the diabetic heart. Genome editing is a technology utilized to alter endogenous genes. Genome editing also provides an option to induce cardioprotective genes or inhibit genes linked to adverse cardiac remodeling and thus has promise in ameliorating DMCM. Non-coding genes have emerged as novel regulators of cellular signaling and may serve as potential therapeutic targets for DMCM. Specifically, there is a widespread change in the gene expression of fetal cardiac genes and microRNAs, termed genetic reprogramming, that promotes pathological remodeling and contributes to heart failure in diabetes. This genetic reprogramming of both coding and non-coding genes varies with the progression and severity of DMCM. Thus, genetic editing provides a promising option to investigate the role of specific genes/non-coding RNAs in DMCM initiation and progression as well as developing therapeutics to mitigate cardiac remodeling and ameliorate DMCM. This chapter will summarize the research progress in genome editing and DMCM and provide future directions for utilizing genome editing as an approach to prevent and/or treat DMCM.
© 2023. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
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The efficacy and safety of traditional Chinese medicine treating diabetic cardiomyopathy: A protocol for systematic review and meta-analysis.
Medicine (Baltimore)2022 Nov;101(47):e31269. doi: 10.1097/MD.0000000000031269.
Han Shuo, Hou Yuan, Liu Huaman, Zhao Quanlin,
Abstract
BACKGROUND:
Diabetic cardiomyopathy, secondary to diabetes, is the main cause of death in patients with diabetes. In China, traditional Chinese medicine has achieved good performance in treating diabetic cardiomyopathy. However, to date, no systematic review or meta-analysis has been published on the treatment of diabetic cardiomyopathy by traditional Chinese medicine.
METHODS:
This study strictly followed the preferred guidelines for systematic review. Two researchers searched seven databases: EMbase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, and WANFANG Database. The retrieval time limit ranged from the establishment of the database to August 2022. All clinical randomized controlled trials that met the inclusion and exclusion criteria were included in this study. Statistical analysis was performed using RevMan 5.3.
RESULTS:
This study analyzed the clinical efficacy and safety of traditional Chinese medicine in the treatment of diabetic cardiomyopathy.
CONCLUSION:
The results of this study provide evidence-based medical evidence for the clinical use of traditional Chinese medicine in the treatment of diabetic heart disease in the future.
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
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LncRNA TUG1 exacerbates myocardial fibrosis in diabetic cardiomyopathy by modulating the microRNA-145a-5p/Cfl2 axis.
J Cardiovasc Pharmacol2022 Nov;():. doi: 10.1097/FJC.0000000000001391.
Wang KunWei, Lin Yingnan, Shen Honghui, Yu Shushu, Xu Jiahong,
Abstract
Nowadays, there is limited prevention and treatment for myocardial fibrosis in diabetic cardiomyopathy (DCM). Our study aimed to depict the mechanism of the lncRNA TUG1/miR-145a-5p/Cfl2 axis in DCM and to provide a molecular basis for the study of this disease. Male C57BL/6J mice were intraperitoneally injected with streptozotocin to establish DCM mouse models. The expression levels of lncRNA TUG1, miR-145a-5p, and Cfl2 in myocardial tissues of mice were tested by RT-qPCR or Western blot. Cardiac function was assessed by echocardiography. The contents of Ang-II, TNF-?, and IL-1? were measured using ELISA. The histopathological observation was performed by HE staining and Masson staining. The expression levels of myocardial fibrosis-related genes COL1A1, MMP2, and FN1 were determined by RT-qPCR. In addition, bioinformatics website, RIP assay, pull down assay, and luciferase activity assay were conducted to verify the relationships of lncRNA TUG1, miR-145a-5p, and Cfl2. In the DCM mouse model, lncRNA TUG1 and Cfl2 expression levels were up-regulated and miR-145a-5p expression was down-regulated. Down-regulation of lncRNA TUG1 improved cardiac function and myocardial fibrosis, decreased COL1A1, MMP2, and FN1 expression levels, as well as TNF-?, IL-1?, and Ang-II contents in myocardial tissues of DCM mice. Up-regulation of miR-145a-5p showed the same trend as down-regulation of lncRNA TUG1. Additionally, up-regulating miR-145a-5p reversed the promotion roles of lncRNA TUG1 on myocardial fibrosis in DCM mice, and up-regulating Cfl2 compromised the improvement effect of down-regulated lncRNA TUG1 on myocardial fibrosis in DCM mice. Mechanistically, there was a binding site between lncRNA TUG1 and miR-145a-5p, and miR-145a- 5p had a targeting relationship with Cfl2. This study highlights that lncRNA TUG1 sponges miR-145a-5p to aggravate myocardial fibrosis in DCM mice by promoting Cfl2.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries.
Circulation2022 Nov;():. doi: 10.1161/CIRCULATIONAHA.122.059304.
Gao Pan, Cao Mengying, Jiang Xueli, Wang Xiaolin, Zhang Guoping, Tang Xinru, Yang Chunjie, Komuro Issei, Ge Junbo, Li Liliang, Zou Yunzeng,
Abstract
BACKGROUND:
Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway.
METHODS:
Type 2 diabetes models were established using leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein-coupled receptor-targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies.
RESULTS:
Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase-mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes , , and . Under hyperglycemic conditions, high glucose induced CB2R internalization in a ?-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries.
CONCLUSIONS:
CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.
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Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-? signaling.
Theranostics2022 ;12(17):7250-7266. doi: 10.7150/thno.77043.
Zhang Yan, Cao Yang, Zheng Rui, Xiong Zhenyu, Zhu Zhengru, Gao Fanya, Man Wanrong, Duan Yu, Lin Jie, Zhang Xuebin, Wu Dexi, Jiang Mengyuan, Zhang Xiao, Li Congye, Gu Xiaoming, Fan Yanhong, Sun Dongdong,
Abstract
Extracellular matrix (ECM) remodeling, a key pathological feature in diabetic cardiomyopathy (DCM), is triggered by oxidative stress, inflammation, and various metabolic disorders in the heart. Cardiac fibroblasts (CFs) are the primary source of ECM proteins and the ultimate effector cells in ECM remodeling. CFs are turned on and differentiated into myofibroblasts in response to profibrotic signaling. Rnd3 is a small Rho-GTPase involved in the regulation of cell-cycle distribution, cell migration, and cell morphogenesis. Emerging evidence suggests a link between Rnd3 expression and onset of cardiovascular diseases. However, the role of Rnd3 in DCM remains unknown. Flow cytometry was employed to separate different types of cardiac cells. Type 2 diabetes mellitus was established in Rnd3 fibroblast-specific knockout and transgenic mice. RNA sequencing and chromatin immunoprecipitation assay were used to discern signaling pathways involved. Rnd3 expression was reduced in cardiac tissues of diabetic mice, with CFs being the primary cell type. Fibroblast-specific upregulation of Rnd3 was protective against DCM, whereas Rnd3 downregulation in fibroblasts accentuated cardiac oxidative stress, fibrosis, ventricular remodeling, and dysfunction. Moreover, Rnd3 overexpression significantly attenuated reactive oxygen species production, CF migration and proliferation under high levels of glucose (35 mmol/L) and palmitic acid (500 µmol/L) challenge. Furthermore, RNA sequencing indicated that Notch and TGF-? signaling were significantly suppressed upon Rnd3 overexpression. Mechanistically, Rnd3 regulated Notch and TGF-? signaling by interacting with NICD and ROCK1, respectively. Specifically, glucotoxicity and lipotoxicity control Rnd3 expression by regulating the binding of Nr1H2 and Rnd3 promoter. Our findings provide compelling evidence in that fibroblast-specific activation of Rnd3 protects against cardiac remodeling in DCM, indicating promises of targeting Rnd3 in the treatment of DCM.
© The author(s).
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Cardioprotective effects of neuropeptide galanin: Focusing on its roles against diabetic heart.
Peptides2022 Nov;159():170918. doi: 10.1016/j.peptides.2022.170918.
She Yuqing, Ge Ran, Gu Xuewen, Fang Penghua, Zhang Zhenwen,
Abstract
Following an unprecedented rise in the number of the aged, the incidence of age-related diseases, such as diabetes and cardiovascular disease, is consequently increasing in the world. Type 2 diabetes mellitus (T2DM) is associated with excess cardiovascular morbidity and mortality. The diabetic heart is characterized by increased cardiomyocyte stiffness and fibrotic changes. Despite many factors resulting in cardiomyocyte injury and dysfunction in diabetes, insulin resistance is still a critical etiology of diabetic cardiomyopathy. Preclinical and clinical studies have revealed an intriguing role for galanin in the pathogenesis of insulin resistance and diabetic heart disease. A significant change in plasma galanin levels occurred in patients suffering from type 2 diabetes or cardiomyocyte injury. In turn, galanin may also distinctly mitigate hyperglycemia and insulin resistance in diabetes as well as increase glucose metabolism and mitochondrial biogenesis in cardiac muscle. Here, we critically review current data about the multivariate relationship among galanin, insulin resistance, and cardiac muscle to comprehensively evaluate the protective role of galanin and its receptors for the diabetic heart and to determine whether galanin receptor 2 agonists potentially represent a feasible way to treat diabetic cardiomyopathy in the future.
Copyright © 2022 Elsevier Inc. All rights reserved.
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Inhibition of Toll-like Receptor-4 expression for amelioration of myocardial injury in diabetes: A meta-analysis.
Clinics (Sao Paulo)2022 ;77():100137. doi: 10.1016/j.clinsp.2022.100137.
Yuan Jinxin, Yin Xingwen, Jiang Hua,
Abstract
To understand the relationship between the inhibition of Toll-Like Receptor-4 (TLR4) expression levels and diabetic myocardial injury, studies on TLR4 and diabetic myocardial injury in the China National Knowledge Internet (CNKI), WanFang database, VIP Database, PubMed, The Cochrane Library, Web of Science, and other databases were explored (retrieval details: November 2020). A meta-analysis of the selected literature was performed using the RevMan 5.4 software to detect publication bias using funnel plots and conduct a sensitivity analysis. Nine publications were finally included in this study, of which six included data on Heart Weight/Body Weight (HW/BW) indexes, and five included data on Left Ventricular Systolic Pressure (LVSP) and Left Ventricular End-Diastolic Pressure (LVEDP) indices. The meta-analysis showed that HW/BW was significantly reduced after the suppression of TLR4 expression (Standardized Mean Difference [SMD?=?1.9], 95% CI between 0.59 and 3.21, p?=?0.004), LVSP was significantly improved (SMD?=?-2.39, 95% CI between -4.32 and -0.46, p?=?0.02), and LVEDP was significantly reduced (SMD?=?2.88, 95% CI between 1.05 and 4.71, p?=?0.002). The TLR4 signaling pathway plays an essential role in the pathogenesis of Diabetic Cardiomyopathy (DCM). Inhibition of TLR4 expression can improve the degree of cardiac impairment. TLR4 may become a new target for the treatment of DCM, and the use of TLR4 inhibitors may prove to be a novel strategy for therapeutic research.
Copyright © 2022. Published by Elsevier España, S.L.U.
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High Glucose-Induced Cardiomyocyte Damage Involves Interplay between Endothelin ET-1/ET/ET Receptor and mTOR Pathway.
Int J Mol Sci2022 Nov;23(22):. doi: 13816.
Pandey Sudhir, Madreiter-Sokolowski Corina T, Mangmool Supachoke, Parichatikanond Warisara,
Abstract
Patients with type two diabetes mellitus (T2DM) are at increased risk for cardiovascular diseases. Impairments of endothelin-1 (ET-1) signaling and mTOR pathway have been implicated in diabetic cardiomyopathies. However, the molecular interplay between the ET-1 and mTOR pathway under high glucose (HG) conditions in H9c2 cardiomyoblasts has not been investigated. We employed MTT assay, qPCR, western blotting, fluorescence assays, and confocal microscopy to assess the oxidative stress and mitochondrial damage under hyperglycemic conditions in H9c2 cells. Our results showed that HG-induced cellular stress leads to a significant decline in cell survival and an impairment in the activation of ET-R/ET-R and the mTOR main components, Raptor and Rictor. These changes induced by HG were accompanied by a reactive oxygen species (ROS) level increase and mitochondrial membrane potential (MMP) loss. In addition, the fragmentation of mitochondria and a decrease in mitochondrial size were observed. However, the inhibition of either ET-R alone by ambrisentan or ET-R/ET-R by bosentan or the partial blockage of the mTOR function by silencing Raptor or Rictor counteracted those adverse effects on the cellular function. Altogether, our findings prove that ET-1 signaling under HG conditions leads to a significant mitochondrial dysfunction involving contributions from the mTOR pathway.
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Molecular Mechanisms and Promising Role of Dihydromyricetin in Cardiovascular Diseases.
Physiol Res2022 Nov;():.
Nie H, Ji T, Fu J, Chen D, Tang Z, Zhang C,
Abstract
Vine tea, a Chinese herbal medicine, is widely used in traditional Asian medicine to treat common health problems. Dihydromyricetin (DMY) is the main functional flavonoid compound extracted from vine tea. In recent years, preclinical studies have focused on the potential beneficial effects of dihydromyricetin, including glucose metabolism regulation, lipid metabolism regulation, neuroprotection, and anti-tumor effects. In addition, DMY may play a role in cardiovascular disease by resisting oxidative stress and participating in the regulation of inflammation. This review is the first review that summaries the applications of dihydromyricetin in cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial hypertrophy, and diabetic cardiomyopathy. We also clarified the underlying mechanisms and signaling pathways involved in the above process. The aim of this review is to provide a better understanding and quick overview for future researches of dihydromyricetin in the field of cardiovascular diseases, and more detailed and robust researches are needed for evaluation and reference.
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Luteolin Attenuates Diabetic Myocardial Hypertrophy by Inhibiting Proteasome Activity.
Pharmacology2022 Nov;():1-14. doi: 10.1159/000527201.
Li Xiao-Bing, Rekep Mubarak, Tian Jia-Hui, Wu Qian, Chen Mei, Yang Shuo, Zhang Lu-Xuan, Zhang Gui-Ping, Qin Yuan, Yu Xi-Yong, Xue Qin, Liu Ying-Hua,
Abstract
INTRODUCTION:
Luteolin is a flavonoid polyphenolic compound exerting broad pharmacological and medicinal properties. Diabetes-related obesity increases the total blood volume and cardiac output and may increase the myocardial hypertrophy progression. However, the mechanism of luteolin in diabetic myocardial hypertrophy remains uncertain. Therefore, this study aimed to evaluate whether luteolin improved diabetic cardiomyopathy (DCM) by inhibiting the proteasome activity.
METHODS:
Cardiomyopathy was induced in streptozotocin-treated diabetes mellitus (DM) and db/db mice. Luteolin (20 mg kg-1·day-1) was administrated via gavage for 12 weeks. In vitro, high glucose and high insulin (HGI, glucose at 25.5 mM and insulin at 0.1 µM) inducing primary neonatal rat cardiomyocytes (NRCMs) were treated with or without luteolin for 48 h. Echocardiography, reverse transcription quantitative polymerase chain reaction, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate.
RESULTS:
Luteolin administration significantly prevented the onset of cardiac hypertrophy, fibrosis, and dysfunction in type 1 DM (T1DM) and type 2 DM (T2DM). Compared with DCM mice, luteolin groups showed lower serum triglyceride and total cholesterol levels. Furthermore, luteolin attenuated HGI-induced myocardial hypertrophy and reduced atrial natriuretic factor mRNA level in NRCMs. Proteasome activities were inhibited by luteolin in vitro. Luteolin also reduces the proteasome subunit levels (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome, as well as proteasome-regulated particles (Rpt) 1 and Rpt4 levels of 19S proteasome. Furthermore, luteolin treatment increased protein kinase B (AKT) and GSK-3?/? (inactivation of GSK-3) phosphorylation. The phosphorylation level of AMPK activity was also reversed after the treatment with luteolin in comparison with the HGI-treated group.
CONCLUSION:
This study indicates that luteolin protected against DCM in mice, including T1DM and T2DM, by upregulating phosphorylated protein AMPK and AKT/GSK-3 pathways while decreasing the proteasome activity. These findings suggest that luteolin may be a potential therapeutic agent for DCM.
© 2022 S. Karger AG, Basel.
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Multi-modality cardiac imaging in the management of diabetic heart disease.
Front Cardiovasc Med2022 ;9():1043711. doi: 1043711.
Wamil Malgorzata, Goncalves Marcos, Rutherford Alexander, Borlotti Alessandra, Pellikka Patricia Ann,
Abstract
Diabetic heart disease is a major healthcare problem. Patients with diabetes show an excess of death from cardiovascular causes, twice as high as the general population and those with diabetes type 1 and longer duration of the disease present with more severe cardiovascular complications. Premature coronary artery disease and heart failure are leading causes of morbidity and reduced life expectancy. Multimodality cardiac imaging, including echocardiography, cardiac computed tomography, nuclear medicine, and cardiac magnetic resonance play crucial role in the diagnosis and management of different pathologies included in the definition of diabetic heart disease. In this review we summarise the utility of multi-modality cardiac imaging in characterising ischaemic and non-ischaemic causes of diabetic heart disease and give an overview of the current clinical practice. We also describe emerging imaging techniques enabling early detection of coronary artery inflammation and the non-invasive characterisation of the atherosclerotic plaque disease. Furthermore, we discuss the role of MRI-derived techniques in studying altered myocardial metabolism linking diabetes with the development of diabetic cardiomyopathy. Finally, we discuss recent data regarding the use of artificial intelligence applied to large imaging databases and how those efforts can be utilised in the future in screening of patients with diabetes for early signs of disease.
Copyright © 2022 Wamil, Goncalves, Rutherford, Borlotti and Pellikka.
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Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy.
JMA J2022 Oct;5(4):407-415. doi: 10.31662/jmaj.2022-0155.
Ketenci Melis, Zablocki Daniela, Sadoshima Junichi,
Abstract
One of the major complications of diabetes mellitus is diabetic cardiomyopathy. One of the mechanisms that initiates the irreversible deterioration of cardiac function in diabetic cardiomyopathy is mitochondrial dysfunction. Functionally impaired mitochondria result in greater levels of oxidative stress and lipotoxicity, both of which exacerbate mitochondrial damage. Mitochondrial health is constantly monitored by mitochondrial quality control mechanisms. Mitophagy selectively degrades damaged mitochondria, thereby maintaining the healthy pool of mitochondria and preserving myocardial function. Mitophagy in diabetic cardiomyopathy is mediated by multiple mechanisms in a time-dependent manner. Potential targets for the treatment of diabetic cardiomyopathy include increased oxidative stress, mitochondrial dynamics, and mitochondrial clearance. Thus, stimulation of mitophagy represents a promising strategy for the alleviation of diabetic cardiomyopathy.
Copyright © Japan Medical Association.
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The importance of caveolin as a target in the prevention and treatment of diabetic cardiomyopathy.
Front Immunol2022 ;13():951381. doi: 951381.
Xia Weiyi, Li Xia, Wu Qingping, Xu Aimin, Zhang Liangqing, Xia Zhengyuan,
Abstract
The diabetic population has been increasing in the past decades and diabetic cardiomyopathy (DCM), a pathology that is defined by the presence of cardiac remodeling and dysfunction without conventional cardiac risk factors such as hypertension and coronary heart diseases, would eventually lead to fatal heart failure in the absence of effective treatment. Impaired insulin signaling, commonly known as insulin resistance, plays an important role in the development of DCM. A family of integral membrane proteins named caveolins (mainly caveolin-1 and caveolin-3 in the myocardium) and a protein hormone adiponectin (APN) have all been shown to be important for maintaining normal insulin signaling. Abnormalities in caveolins and APN have respectively been demonstrated to cause DCM. This review aims to summarize recent research findings of the roles and mechanisms of caveolins and APN in the development of DCM, and also explore the possible interplay between caveolins and APN.
Copyright © 2022 Xia, Li, Wu, Xu, Zhang and Xia.
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Heart Failure-Type Symptom Score Trajectories in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.
Am J Kidney Dis2022 Nov;():. doi: S0272-6386(22)01041-1.
Walther Carl P, Benoit Julia S, Bansal Nisha, Nambi Vijay, Navaneethan Sankar D, ,
Abstract
RATIONALE & OBJECTIVE:
Quality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individual with CKD to understand the patterns and trajectories of HF-type symptoms in this setting.
STUDY DESIGN:
Prospective cohort study.
SETTING & PARTICIPANTS:
3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF.
PREDICTORS:
Sociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and EKG parameters.
OUTCOMES:
Trajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire [KCCQ] Overall Summary Score with a range of 0-100 where
ANALYTICAL APPROACH:
Latent class mixed models were used to model trajectories. Multinomial logistic regression was used to model relationships of predictors with trajectory group membership.
RESULTS:
Five trajectories of KCCQ score were identified in the cohort of 3,044 adults, 45% of whom were female, and whose median age was 61 years. Group 1 (41.7%) had a stable high score (minimal symptoms, average score of 96); Groups 2 (35.6%) and 3 (15.6%) had stable but lower scores (mild symptoms, average 81, and clinically significant symptoms, average 52, respectively). Group 4 (4.9%) had a substantial worsening in symptoms over time (mean 31-point decline) and Group 5 (2.2%) had a substantial improvement (mean 33-point increase) in KCCQ score. A majority of Group 1 was male, non-diabetic, non-obese, and had higher baseline kidney function. A majority of Groups 2 and 3 had diabetes and obesity. A majority of Group 4 was male and had substantial proteinuria. Group 5 had the highest proportion of baseline cardiovascular disease (CVD).
LIMITATIONS:
No validation cohort available, CKD management changes in recent years may alter trajectories, and latent class models depend on the missing at random assumption.
CONCLUSIONS:
Distinct HF-type symptom burden trajectories were identified in the setting of CKD, corresponding to different baseline characteristics. These results highlight the diversity of HF-type symptom experiences in individuals with CKD.
Copyright © 2022. Published by Elsevier Inc.
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