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Pubblicazioni recenti - diabetic cardiomyopathy
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Pharmacological modulation of the hydrogen sulfide (H S) system by dietary H S-donors: A novel promising strategy in the prevention and treatment of type 2 diabetes mellitus.
Phytother Res2020 Oct;():. doi: 10.1002/ptr.6923.
Piragine Eugenia, Calderone Vincenzo,
Abstract
Type 2 diabetes mellitus (T2DM) represents the most common age-related metabolic disorder, and its management is becoming both a health and economic issue worldwide. Moreover, chronic hyperglycemia represents one of the main risk factors for cardiovascular complications. In the last years, the emerging evidence about the role of the endogenous gasotransmitter hydrogen sulfide (H S) in the pathogenesis and progression of T2DM led to increasing interest in the pharmacological modulation of endogenous "H S-system". Indeed, H S directly contributes to the homeostatic maintenance of blood glucose levels; moreover, it improves impaired angiogenesis and endothelial dysfunction under hyperglycemic conditions. Moreover, H S promotes significant antioxidant, anti-inflammatory, and antiapoptotic effects, thus preventing hyperglycemia-induced vascular damage, diabetic nephropathy, and cardiomyopathy. Therefore, H S-releasing molecules represent a promising strategy in both clinical management of T2DM and prevention of macro- and micro-vascular complications associated to hyperglycemia. Recently, growing attention has been focused on dietary organosulfur compounds. Among them, garlic polysulfides and isothiocyanates deriving from Brassicaceae have been recognized as H S-donors of great pharmacological and nutraceutical interest. Therefore, a better understanding of the therapeutic potential of naturally occurring H S-donors may pave the way to a more rational use of these nutraceuticals in the modulation of H S homeostasis in T2DM.
© 2020 John Wiley & Sons Ltd.
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Calcium Signaling in Endocardial and Epicardial Ventricular Myocytes from Streptozotocin-Induced Diabetic Rat.
J Diabetes Investig2020 Oct;():. doi: 10.1111/jdi.13451.
Al Kury Lina T, Sydorenko Vadym, Smail Manal Ma, Qureshi Muhammad A, Shmygol Anatoly, Papandreou Dimitrios, Singh Jaipaul, Howarth Frank Christopher,
Abstract
AIMS/INTRODUCTION:
Abnormalities in Ca signaling have a key role in hemodynamic dysfunction in diabetic heart. The purpose of this study was to explore the effects of streptozotocin (STZ) - induced diabetes on Ca signaling in epicardial (EPI) and endocardial (ENDO) cells of the left ventricle, after 5-6 months of STZ injection.
MATERIALS AND METHODS:
Whole-cell patch clamp was used to measure L-type Ca channel (LTCC) and Na /Ca exchanger (NCX) currents. Fluorescence photometry techniques were used to measure intracellular free Ca concentration [Ca ] .
RESULTS:
Although LTCC current was not significantly altered, the amplitude (AMP) of Ca transients increased significantly in EPI-STZ and ENDO-STZ compared to controls. Time to peak (TPK) LTCC current, TPK Ca transient, time to half (THALF) decay of LTCC current and THALF decay of Ca transients were not significantly changed in EPI-STZ and ENDO-STZ myocytes compared to controls. NCX current was significantly smaller in EPI-STZ and in ENDO-STZ compared to controls.
CONCLUSIONS:
STZ-induced diabetes resulted in an increase in AMP of Ca transients in EPI and ENDO myocyte that was independent of LTCC current. Such an effect can be attributed, at least in part, to the dysfunction of NCX. Additional studies are warranted to improve our understanding of the regional impact of diabetes on Ca signaling, which will facilitate the discovery of new targeted treatments for diabetic cardiomyopathy.
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MALAT1-mediated recruitment of the histone methyltransferase EZH2 to the microRNA-22 promoter leads to cardiomyocyte apoptosis in diabetic cardiomyopathy.
Sci Total Environ2020 Sep;():142191. doi: S0048-9697(20)35720-X.
Wang Chong, Liu Guibo, Yang Heran, Guo Sufen, Wang Hongwei, Dong Zhihui, Li Xinxin, Bai Yuxin, Cheng Yongxia,
Abstract
Diabetic patients often have a heightened risk of cardiomyopathy, even in the absence of traditional risk factors such as hypertension and atherosclerotic coronary artery disease. Diabetic cardiomyopathy is characterized by a typical cardiomyopathy specific to diabetes, the pathogenesis of which has yet to be fully elucidated. As a well-documented oncogenic long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in a variety of pathological processes, including diabetic complications. This study aimed to evaluate the functional roles of MALAT1 in the pathogenesis of diabetic cardiomyopathy. Spontaneously diabetic (db/db) C57BL/Ks mice were employed to establish diabetic cardiomyopathy models in vivo and high glucose (HG)-cultured mouse cardiomyocytes for myocardial damage models in vitro. Mouse left ventricular volume and function were evaluated by echocardiography, while the myocyte cross-sectional area was calculated to evaluate the degree of myocardial hypertrophy. TUNEL staining and flow cytometric analysis were performed to evaluate myocardial damage and cardiomyocyte apoptosis. Silencing of MALAT1 was found to attenuate cardiac dysfunction and inhibit cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes. MALAT1 recruited the histone methyltransferase EZH2 to the miR-22 promoter region and inhibited its expression. EZH2 induced an increased in the expression of ATP-binding cassette transporter A1 (ABCA1), which was identified to be a target gene of miR-22. Silencing of EZH2 was found to improve cardiac function and prevent cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes in the presence of MALAT1, suggesting that MALAT1 mediated myocardial damage by recruiting EZH2 to the miR-22 promoter. Taken together, this study's findings provide evidence confirming our hypothesis, suggesting the involvement of MALAT1 in the processes of cardiac function and cardiomyocyte apoptosis via the EZH2/miR-22/ABCA1 signaling cascade, which has potential therapeutic implications for the understanding of diabetic cardiomyopathy.
Copyright © 2020. Published by Elsevier B.V.
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Protective effects of BiP inducer X (BIX) against diabetic cardiomyopathy in rats.
Can J Physiol Pharmacol2020 Oct;():. doi: 10.1139/cjpp-2020-0419.
Idari Gholamreza, Karimi Pouran, Ghaffari Samad, Hashemy Seyed Isaac, Mashkani Baratali,
Abstract
Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of pro-caspase 3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.
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Left atrial dysfunction and stiffness in pediatric and adult patients with type 1 diabetes mellitus assessed with speckle tracking echocardiography.
Pediatr Diabetes2020 Oct;():. doi: 10.1111/pedi.13141.
Ifuku Mayumi, Takahashi Ken, Hosono Yu, Iso Takeshi, Ishikawa Akimi, Haruna Hidenori, Takubo Noriyuki, Komiya Kouji, Kurita Mika, Ikeda Fuki, Watada Hirotaka, Shimizu Toshiaki,
Abstract
BACKGROUND:
Subclinical diastolic dysfunction in patients with type 1 diabetes mellitus (T1DM) caused by myocardial injury due to diabetic cardiomyopathy leads to a high risk of death and heart failure. This myocardial injury extends not only to the left ventricle (LV) but also to the left atrium (LA). However, LA function in children and young adults with T1DM has not been extensively studied.
OBJECTIVE:
Therefore, the aim of this study was to assess LA dysfunction in pediatric and adult patients with T1DM usingLA strain analysis withechocardiography.
SUBJECTS:
Fifty-three patients (median age: 23 [range: 5-41] years) with T1DM.
METHODS:
We dividedthe patients into three age groups (D1: 5-14?years, D2: 15-24?years, D3: 25-41?years);53 age- and sex-matched controls were divided into three corresponding groups (C1, C2, and C3). LA and LV functions were evaluated usingechocardiography.
RESULTS:
LA reservoir strain was lower in the D2 and D3 groups than in the C2 and C3 groups (p = 0.001, p = 0.004, respectively). LA conduit strain was lower in the D2 group thanin the C2 group (p = 0.002). LA stiffness wassignificantlygreater in the D3 groupthan in the C3 group (p
CONCLUSIONS:
In patients with T1DM, LA phasic function decreased in adolescents and young adults, and LA stiffness increased in adult patients aged>30?years. LA phasic function and LA stiffness can be potentially used as early markers for diastolic dysfunction. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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LncRNA GAS5 inhibits NLRP3 inflammasome activation-mediated pyroptosis in diabetic cardiomyopathy by targeting miR-34b-3p/AHR.
Cell Cycle2020 Oct;():1-12. doi: 10.1080/15384101.2020.1831245.
Xu Yingying, Fang Haiyang, Xu Qin, Xu Congcong, Yang Lu, Huang Chahua,
Abstract
Long noncoding RNA GAS5 is down-regulated in cardiomyocytes in diabetic cardiomyopathy (DCM). Here, we studied the involvement of GAS5 in DCM by analyzing its expression in DCM mouse model and cardiac muscle cell line (HL-1 cells). Compared with normal mice, GAS5 was severely down-regulated in heart tissues of DCM mice. GAS5 overexpression improved cardiac function and myocardial hypertrophy in DCM mice. In addition, the expression of NLRP3, caspase-1, Pro-caspase-1, IL-1? and IL-18 were increased in heart tissues of DCM mice and high glucose-treated HL-1 cells, which was repressed by GAS5 up-regulation. GAS5 overexpression suppressed caspase-1 activity, LDH release and the levels of IL-1?, IL-18 in the high glucose-treated HL-1 cells. Moreover, GAS5 regulated AHR expression by sponging miR-34b-3p. Furthermore, GAS5 overexpression suppressed NLRP3 inflammasome activation-mediated pyroptosis by regulating miR-34b-3p/AHR axis. In summary, our study demonstrates that GAS5 acts as a competing endogenous RNA to enhance AHR expression by sponging miR-34b-3p, which consequently represses NLRP3 inflammasome activation-mediated pyroptosis to improve DCM. Thus, our data provide a novel lncRNA GAS5 that could be a valuable target for DCM treatment.
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A systematic review of post-translational modifications in the mitochondrial permeability transition pore complex associated with cardiac diseases.
Biochim Biophys Acta Mol Basis Dis2020 Oct;():165992. doi: S0925-4439(20)30340-9.
Alves-Figueiredo H, Silva-Platas C, Lozano O, Vázquez-Garza E, Guerrero-Beltrán C E, Zarain-Herzberg A, García-Rivas G,
Abstract
The mitochondrial permeability transition pore (mPTP) opening is involved in the pathophysiology of multiple cardiac diseases, such as ischemia/reperfusion injury and heart failure. A growing number of evidence provided by proteomic screening techniques has demonstrated the role of post-translational modifications (PTMs) in several key components of the pore in response to changes in the extra/intracellular environment and bioenergetic demand. This could lead to a fine, complex regulatory mechanism that, under pathological conditions, can shift the state of mitochondrial functions and, thus, the cell's fate. Understanding the complex relationship between these PTMs is still under investigation and can provide new, promising therapeutic targets and treatment approaches. This review, using a systematic review of the literature, presents the current knowledge on PTMs of the mPTP and their role in health and cardiac disease.
Copyright © 2020. Published by Elsevier B.V.
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Phosphatidylinositol 4-kinase III? mediates contraction-induced GLUT4 translocation and shows its anti-diabetic action in cardiomyocytes.
Cell Mol Life Sci2020 Oct;():. doi: 10.1007/s00018-020-03669-7.
Sun A, Simsek Papur O, Dirkx E, Wong L, Sips T, Wang S, Strzelecka A, Nabben M, Glatz J F C, Neumann D, Luiken J J F P,
Abstract
In the diabetic heart, long-chain fatty acid (LCFA) uptake is increased at the expense of glucose uptake. This metabolic shift ultimately leads to insulin resistance and a reduced cardiac function. Therefore, signaling kinases that mediate glucose uptake without simultaneously stimulating LCFA uptake could be considered attractive anti-diabetic targets. Phosphatidylinositol-4-kinase-III? (PI4KIII?) is a lipid kinase downstream of protein kinase D1 (PKD1) that mediates Golgi-to-plasma membrane vesicular trafficking in HeLa-cells. In this study, we evaluated whether PI4KIII? is involved in myocellular GLUT4 translocation induced by contraction or oligomycin (an FF-ATP synthase inhibitor that activates contraction-like signaling). Pharmacological targeting, with compound MI14, or genetic silencing of PI4KIII? inhibited contraction/oligomycin-stimulated GLUT4 translocation and glucose uptake in cardiomyocytes but did not affect CD36 translocation nor LCFA uptake. Addition of the PI4KIII? enzymatic reaction product phosphatidylinositol-4-phosphate restored oligomycin-stimulated glucose uptake in the presence of MI14. PI4KIII? activation by PKD1 involves Ser294 phosphorylation and altered its localization with unchanged enzymatic activity. Adenoviral PI4KIII? overexpression stimulated glucose uptake, but did not activate hypertrophic signaling, indicating that unlike PKD1, PI4KIII? is selectively involved in GLUT4 translocation. Finally, PI4KIII? overexpression prevented insulin resistance and contractile dysfunction in lipid-overexposed cardiomyocytes. Together, our studies identify PI4KIII? as positive and selective regulator of GLUT4 translocation in response to contraction-like signaling, suggesting PI4KIII? as a promising target to rescue defective glucose uptake in diabetics.
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[Research progress on the association between myocardial fibroblast transdifferentiation and diabetic cardiomyopathy].
Zhonghua Xin Xue Guan Bing Za Zhi2020 Oct;48(10):885-889. doi: 10.3760/cma.j.cn112148-20191027-00659.
Gao J M, Hu B, Shen E,
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Si-Miao-Yong-An decoction preserves cardiac function and regulates GLC/AMPK/NF-?B and GLC/PPAR?/PGC-1? pathways in diabetic mice.
Biomed Pharmacother2020 Oct;132():110817. doi: S0753-3322(20)31010-6.
Li Lin, Chen Xiangyang, Su Congping, Wang Qing, Li Rui, Jiao Wenchao, Luo Hui, Tian Yimiao, Tang Jiayang, Li Xiaoxuan, Liu Bin, Wang Wei, Zhang Dongwei, Guo Shuzhen,
Abstract
BACKGROUND:
Diabetic cardiomyopathy (DCM) is a main cause of heart failure and death in diabetic patients. However, countermeasures to limit the development of this disease remain insufficient. Si-Miao-Yong-An decoction (SMYA), a Chinese herbal prescription, exhibits both lipid-lowering and cardiovascular preserving effects, and may have an effect on DCM management.
PURPOSE:
The current study is aimed to investigate the effects of SMYA on the cardiac function in diabetic mice and the underlying mechanisms involved.
METHODS:
Streptozotocin-induced diabetic mice were fed intragastrically with SMYA every day for 15 weeks. Cardiac function was assessed by echocardiograph. Histopathological alterations in the heart were determined by hematoxylin/eosin, wheat germ agglutinin, Masson's trichrome, Terminal dUTP nick end-labeling, Oil red O staining, and transmission electron microscopy. The potential involvements of GLC/AMPK/NF-?B and GLC/PPAR?/PGC-1? signaling pathways were investigated by western blot and/or immunohistochemical staining.
RESULTS:
Treatment of diabetic mice with SMYA improved insulin sensitivity, and attenuated the increases of water consumption, food intake, blood glucose, and serum GLC. Furthermore, SMYA ameliorated cardiac systolic and diastolic functions, suppressed the myocardial hypertrophy, fibrosis, apoptosis, inflammation, and lipid accumulation as well as preserved the myofilaments arrangement and mitochondrial integrity. Finally, SMYA downregulated the expressions of GCGR, PGC-1?, PPAR? and the phosphorylation of NF-?B, as well as upregulated the phosphorylation of AMPK in the hearts of diabetic mice.
CONCLUSIONS:
SMYA may ameliorate glucolipid metabolism and cardiac function through the regulation of GLC/AMPK/NF-?B and GLC/PPAR?/PGC-1? signaling pathways in diabetic mice, suggesting that this prescription could provide a new source of drug candidates to protect against DCM.
Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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MALDI-IMS As A Tool to Determine The myocardial Response to Syndecan-2-selected Mesenchymal Stromal Cell Application in An Experimental Model of Diabetic Cardiomyopathy.
Proteomics Clin Appl2020 Oct;():e2000050. doi: 10.1002/prca.202000050.
Pappritz Kathleen, Klein Oliver, Dong Fengquan, Hamdani Nazha, Kovacs Arpad, O'Flynn Lisa, Elliman Steve, O'Brien Timothy, Tschöpe Carsten, Van Linthout Sophie,
Abstract
PURPOSE:
Mesenchymal stromal cells (MSC) are an attractive tool for treatment of diabetic cardiomyopathy. Syndecan-2/CD362 has been identified as a functional marker for MSC isolation. Imaging mass spectrometry (IMS) allows for the characterization of therapeutic responses in the left ventricle. This study aimed to investigate whether IMS can assess the therapeutic effect of CD362 -selected MSC on early onset experimental diabetic cardiomyopathy.
EXPERIMENTAL DESIGN:
1 × 10 wild-type (WT), CD362 , or CD362 MSC were intravenously injected into db/db mice. Four weeks later, mice were hemodynamically characterized and subsequently sacrificed for IMS combined with bottom-up mass spectrometry, and isoform and phosphorylation analyses of cardiac titin.
RESULTS:
Overall alterations of the cardiac proteome signatures, especially titin, were observed in db/db compared to control mice. Interestingly, only CD362 MSC could overcome the reduced titin intensity distribution and shifted the isoform ratio towards the more compliant N2BA form. In contrast, WT and CD362 MSC improved all-titin phosphorylation and protein kinase G activity, which was reflected in an improvement in diastolic performance.
CONCLUSIONS AND CLINICAL RELEVANCE:
IMS enables the characterization of differences in titin intensity distribution following MSC application. However, further analysis of titin phosphorylation is needed to allow for the assessment of the therapeutic efficacy of MSC. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Bakuchiol Alleviates Hyperglycemia-Induced Diabetic Cardiomyopathy by Reducing Myocardial Oxidative Stress via Activating the SIRT1/Nrf2 Signaling Pathway.
Oxid Med Cell Longev2020 ;2020():3732718. doi: 10.1155/2020/3732718.
Ma Wenshuai, Guo Wangang, Shang Fujun, Li Yan, Li Wei, Liu Jing, Ma Chao, Teng Jiwei,
Abstract
Bakuchiol (BAK), a monoterpene phenol reported to have exerted a variety of pharmacological effects, has been related to multiple diseases, including myocardial ischemia reperfusion injury, pressure overload-induced cardiac hypertrophy, diabetes, liver fibrosis, and cancer. However, the effects of BAK on hyperglycemia-caused diabetic cardiomyopathy and its underlying mechanisms remain unclear. In this study, streptozotocin-induced mouse model and high-glucose-treated cell model were conducted to investigate the protective roles of BAK on diabetic cardiomyopathy, in either the presence or absence of SIRT1-specific inhibitor EX527, SIRT1 siRNA, or Nrf2 siRNA. Our data demonstrated for the first time that BAK could significantly abate diabetic cardiomyopathy by alleviating the cardiac dysfunction, ameliorating the myocardial fibrosis, mitigating the cardiac hypertrophy, and reducing the cardiomyocyte apoptosis. Furthermore, BAK achieved its antifibrotic and antihypertrophic actions by inhibiting the TGF-1/Smad3 pathway, as well as decreasing the expressions of fibrosis- and hypertrophy-related markers. Intriguingly, these above effects of BAK were largely attributed to the remarkable activation of SIRT1/Nrf2 signaling, which eventually strengthened cardiac antioxidative capacity by elevating the antioxidant production and reducing the reactive oxygen species generation. However, all the beneficial results were markedly abolished with the administration of EX527, SIRT1 siRNA, or Nrf2 siRNA. In summary, these novel findings indicate that BAK exhibits its therapeutic properties against hyperglycemia-caused diabetic cardiomyopathy by attenuating myocardial oxidative damage via activating the SIRT1/Nrf2 signaling.
Copyright © 2020 Wenshuai Ma et al.
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ethanol leaf extracts protect against diabetic cardiomyopathy in db/db mice via regulating PI3K/Akt/NF-?B signaling.
Food Nutr Res2020 ;64():. doi: 10.29219/fnr.v64.4267.
Wang Yang, Zheng Xiaojie, Li Longyu, Wang Hong, Chen Keyuan, Xu Mingjie, Wu Yiwei, Huang Xueli, Zhang Meiling, Ye Xiaoxia, Xu Tunhai, Chen Rongchang, Zhu Yindi,
Abstract
Background:
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes that can lead to significant mortality. is a tree, the leaves of which are often utilized to prevent and treat diabetes mellitus. Whether leaves can prevent or treat DCM, however, it remains to be formally assessed. The present study was therefore designed to assess the ability of to protect against DCM in db/db mice.
Methods:
Male wild-type (WT) and db/db mice were administered ethanol leaf extracts (ECL) or appropriate vehicle controls daily via gavage, and levels of blood glucose in treated animals were assessed on a weekly basis. After a 10-week treatment, the levels of cardiac troponin I (cTn-I), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), aspartate transaminase (AST), total triglycerides (TG), and total cholesterol (TC) in serum were measured. Activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) and the levels of tumor necrosis factor-? (TNF-?), interleukin-1? (IL-1?), and IL-6 in heart tissues were detected. Hematoxylin-eosin (HE) and Masson staining were conducted. The protein expression that related with oxidative stress and inflammatory reaction was evaluated by Western blotting.
Results:
Compared with WT mice, the TG, TC, and blood glucose levels in db/db mice increased significantly, which were reduced by ECL treatment. Compared with WT mice, the levels of LDH, CK-MB, AST, and cTn-I in serum and MDA in heart tissues of db/db mice increased significantly. Activities of SOD, GSH-Px, and CAT in heart tissues of db/db mice decreased significantly. The levels of inflammatory cytokines (TNF-?, IL-1?, and IL-6) in heart tissues of db/db mice increased remarkably. However, ECL treatment improved the above pathological changes significantly. ECL alleviated pathological injury and fibrosis in heart tissues of mice. Western blotting showed that ECL increased Bcl-2 level and decreased Bax, cle-caspase-3, and cle-caspase-9 expression. Furthermore, ECL inhibited NF-?B nuclear translocation and increased PI3K and p-Akt expressions.
Conclusion:
Our results indicate that ECL treatment can markedly reduce pathological cardiac damage in db/db mice through antiapoptotic, antifibrotic, and anti-inflammatory mechanisms. Specifically, this extract was able to suppress NF-?B activation via the PI3K/Akt signaling pathway. Given its diverse activities and lack of significant side effects, ECL may thus have therapeutic value for the treatment of DCM.
© 2020 Yang Wang et al.
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Incidence of idiopathic cardiomyopathy in patients with type 2 diabetes in Taiwan: age, sex, and urbanization status-stratified analysis.
Cardiovasc Diabetol2020 Oct;19(1):177. doi: 10.1186/s12933-020-01144-y.
Chen Hua-Fen, Chang Ya-Hui, Lo Hsien-Jung, Isfandiari Muhammad Atoillah, Martini Santi, Hou Wen-Hsuan, Li Chung-Yi,
Abstract
BACKGROUND:
The epidemiology of diabetes and idiopathic cardiomyopathy have limited data. We investigated the overall and the age-, sex-, and urbanization-specific incidence and relative hazard of idiopathic cardiomyopathy in association with type 2 diabetes and various anti-diabetic medications used in Taiwan.
METHODS:
A total of 474,268 patients with type 2 diabetes were identified from ambulatory care and inpatient claims in 2007-2009 from Taiwan's National Health Insurance (NHI) database. We randomly selected 474,266 age-, sex-, and diagnosis date-matched controls from the registry of NHI beneficiaries. All study subjects were linked to ambulatory care and inpatient claims (up to the end of 2016) to identify the possible diagnosis of idiopathic cardiomyopathy. The person-year approach with Poisson assumption was used to estimate the incidence, and Cox proportional hazard regression model with Fine and Gray's method was used to estimate the relative hazards of idiopathic cardiomyopathy in relation to type 2 diabetes.
RESULTS:
The overall incidence of idiopathic cardiomyopathy for men and women patients, respectively, was 3.83 and 2.94 per 10,000 person-years, which were higher than the corresponding men and women controls (2.00 and 1.34 per 10,000 person-years). Compared with the control group, patients with type 2 diabetes were significantly associated with an increased hazard of idiopathic cardiomyopathy (adjusted hazard ratio [aHR]: 1.60, 95% confidence interval [CI]: 1.45-1.77] in all age and sex stratifications except in those men aged?>?64 years. Patients with type 2 diabetes aged?
CONCLUSIONS:
In Taiwan, diabetes increased the risk of idiopathic cardiomyopathy in both sexes and in all age groups, except in men aged?>?64 years. Younger patients were vulnerable to have higher HRs of idiopathic cardiomyopathy. Some anti-diabetic medications may reduce the risks of cardiomyopathy.
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Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats.
Int J Mol Sci2020 Oct;21(20):. doi: E7432.
Gliozzi Micaela, Scarano Federica, Musolino Vincenzo, Carresi Cristina, Scicchitano Miriam, Ruga Stefano, Zito Maria Caterina, Nucera Saverio, Bosco Francesca, Maiuolo Jessica, Macrì Roberta, Guarnieri Lorenza, Mollace Rocco, Coppoletta Anna Rita, Nicita Caterina, Tavernese Annamaria, Palma Ernesto, Muscoli Carolina, Mollace Vincenzo,
Abstract
Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX? staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a "frail" myocardial tissue unable to adapt itself to stress.
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Long noncoding RNA PVT1 facilitates high glucose-induced cardiomyocyte death through the miR-23a-3p/CASP10 axis.
Cell Biol Int2020 Oct;():. doi: 10.1002/cbin.11479.
Xia Yin-Wen, Wang Shao-Bo,
Abstract
Dilated cardiomyopathy (DCM) is the leading cause of morbidity and mortality in diabetic patients. Long noncoding RNA plasmacytoma variant translocation 1 (PVT1) has been shown to be related to the pathogenesis of DCM. However, the mechanism by which PVT1 regulates DCM pathogenesis is unclear. High glucose level was employed to construct a DCM cell model in vitro. Cell viability was determined via cell counting kit-8 assay. The level of lactate dehydrogenase (LDH) was measured with the corresponding kit. Expression levels of PVT1, miR-23a-3p, and caspase-10 (CASP10) messenger RNA were evaluated with a quantitative real-time polymerase chain reaction. Cell apoptosis was assessed by flow cytometry assay. Protein levels of B-cell lymphoma 2-associated X (Bax), cleaved-caspase-3 (cleaved-casp-3), and CASP10 were examined via western blot analysis. The relationship between PVT1 or CASP10 and miR-23a-3p was verified with dual-luciferase reporter assay. We observed that PVT1 and CASP10 were upregulated while miR-23a-3p was downregulated in high glucose-induced cardiomyocytes. High glucose levels repressed cardiomyocyte activity and induced cardiomyocyte apoptosis, but this influence was antagonized by PVT1 knockdown or miR-23a-3p overexpression. Furthermore, PVT1 acted as a sponge for miR-23a-3p, and miR-23a-3p inhibition counterbalanced the influence of PVT1 silencing on viability and apoptosis of cardiomyocytes under high glucose level treatment. PVT1 could increase CASP10 expression via sponging miR-23a-3p. In conclusion, PVT1 acted as a deleterious lncRNA in DCM. PVT1 facilitated cardiomyocyte death by regulating the miR-23a-3p/CASP10, which offered a new mechanism to comprehend the pathogenesis of DCM.
© 2020 International Federation for Cell Biology.
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Myocardial Energy Metabolism in Non-ischemic Cardiomyopathy.
Front Physiol2020 ;11():570421. doi: 10.3389/fphys.2020.570421.
Greenwell Amanda A, Gopal Keshav, Ussher John R,
Abstract
As the most metabolically demanding organ in the body, the heart must generate massive amounts of energy adenosine triphosphate (ATP) from the oxidation of fatty acids, carbohydrates and other fuels (e.g., amino acids, ketone bodies), in order to sustain constant contractile function. While the healthy mature heart acts omnivorously and is highly flexible in its ability to utilize the numerous fuel sources delivered to it through its coronary circulation, the heart's ability to produce ATP from these fuel sources becomes perturbed in numerous cardiovascular disorders. This includes ischemic heart disease and myocardial infarction, as well as in various cardiomyopathies that often precede the development of overt heart failure. We herein will provide an overview of myocardial energy metabolism in the healthy heart, while describing the numerous perturbations that take place in various non-ischemic cardiomyopathies such as hypertrophic cardiomyopathy, diabetic cardiomyopathy, arrhythmogenic cardiomyopathy, and the cardiomyopathy associated with the rare genetic disease, Barth Syndrome. Based on preclinical evidence where optimizing myocardial energy metabolism has been shown to attenuate cardiac dysfunction, we will discuss the feasibility of myocardial energetics optimization as an approach to treat the cardiac pathology associated with these various non-ischemic cardiomyopathies.
Copyright © 2020 Greenwell, Gopal and Ussher.
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A Systematic Review of the Pharmacology, Toxicology and Pharmacokinetics of Matrine.
Front Pharmacol2020 ;11():01067. doi: 10.3389/fphar.2020.01067.
You Longtai, Yang Chunjing, Du Yuanyuan, Wang Wenping, Sun Mingyi, Liu Jing, Ma Baorui, Pang Linnuo, Zeng Yawen, Zhang Zhiqin, Dong Xiaoxv, Yin Xingbin, Ni Jian,
Abstract
Matrine (MT) is a naturally occurring alkaloid and an bioactive component of Chinese herbs, such as and Radix . Emerging evidence suggests that MT possesses anti-cancer, anti-inflammatory, anti-oxidant, antiviral, antimicrobial, anti-fibrotic, anti-allergic, antinociceptive, hepatoprotective, cardioprotective, and neuroprotective properties. These pharmacological properties form the foundation for its application in the treatment of various diseases, such as multiple types of cancers, hepatitis, skin diseases, allergic asthma, diabetic cardiomyopathy, pain, Alzheimer's disease (AD), Parkinson's disease (PD), and central nervous system (CNS) inflammation. However, an increasing number of published studies indicate that MT has serious adverse effects, the most obvious being liver toxicity and neurotoxicity, which are major factors limiting its clinical use. Pharmacokinetic studies have shown that MT has low oral bioavailability and short half-life . This review summarizes the latest advances in research on the pharmacology, toxicology, and pharmacokinetics of MT, with a focus on its biological properties and mechanism of action. The review provides insight into the future of research on traditional Chinese medicine.
Copyright © 2020 You, Yang, Du, Wang, Sun, Liu, Ma, Pang, Zeng, Zhang, Dong, Yin and Ni.
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Irisin improves insulin resistance by inhibiting autophagy through the PI3K/Akt pathway in H9c2 cells.
Gene2020 Oct;():145209. doi: S0378-1119(20)30878-7.
Song Rongjing, Zhao Xuecheng, Cao Rong, Liang Yuerun, Zhang Da-Qi, Wang Rong,
Abstract
As an important complication of diabetes mellitus, diabetic cardiomyopathy (DCM) is thought to arise as a result of insulin resistance (IR) in cardiomyocytes. Improving IR in cardiomyocytes may therefore be a way to treat DCM. A recently discovered myokine, irisin, has been shown to be significantly associated with increased insulin sensitivity both in clinical and pre-clinical studies of diabetes mellitus. Based on previously research, we hypothesized that irisin may be a potential candidate for increasing the insulin sensitivity of cardiomyocytes. The aim of the present study was to examine the ability of irisin to affect IR induced by treatment of rat cardiomyocyte H9c2 cells with palmitic acid (PA) and to explore its underlying mechanism. Differentiated H9c2 cells were treated with 500 ?M PA, 200 ng/mL irisin, and 500 ?M PA + 200 ng/mL irisin with or without 100 nM rapamycin (RAP) for 24 h. We found that coincubation with 200 ng/mL irisin for 24 h significantly increased insulin-stimulated glucose consumption compared to the 500 ?M PA group alone. Additionally, coincubation with irisin significantly alleviated the degree of autophagy compared to the 500 ?M PA group alone as evidenced by monodansylcadaverine (MDC) fluorescence, the LC3II/LC3I protein levels ratio, and the protein levels of Atg5 and Atg7. Coincubation with irisin increased the levels of PI3Kp110?, pAkt and Akt compared to the 500 ?M PA group alone. All these effects of irisin were reversed by RAP. Our results indicate that irisin improves IR in H9c2 cells, possibly in part by inhibiting autophagy through activating the PI3K/Akt pathway.
Copyright © 2020 Elsevier B.V. All rights reserved.
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Engineered cardiac tissues: a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy.
Acta Pharmacol Sin2020 Oct;():. doi: 10.1038/s41401-020-00538-8.
Wang Xiang, Chen Xin-Xin, Yu Hai-Tao, Tan Yi, Lin Qian, Keller Bradley B, Zheng Yang, Cai Lu,
Abstract
Rodent diabetic models, used to understand the pathophysiology of diabetic cardiomyopathy (DCM), remain several limitations. Engineered cardiac tissues (ECTs) have emerged as robust 3D in vitro models to investigate structure-function relationships as well as cardiac injury and repair. Advanced glycation end-products (AGEs), produced through glycation of proteins or lipids in response to hyperglycemia, are important pathogenic factor for the development of DCM. In the current study, we developed a murine-based ECT model to investigate cardiac injury produced by AGEs. We treated ECTs composed of neonatal murine cardiac cells with AGEs and observed AGE-related functional, cellular, and molecular alterations: (1) AGEs (150?µg/mL) did not cause acute cytotoxicity, which displayed as necrosis detected by medium LDH release or apoptosis detected by cleaved caspase 3 and TUNEL staining, but negatively impacted ECT function on treatment day 9; (2) AGEs treatment significantly increased the markers of fibrosis (TGF-?, ?-SMA, Ctgf, Collagen I-?1, Collagen III-?1, and Fn1) and hypertrophy (Nppa and Myh7); (3) AGEs treatment significantly increased ECT oxidative stress markers (3-NT, 4-HNE, HO-1, CAT, and SOD2) and inflammation response markers (PAI-1, TNF-?, NF-?B, and ICAM-1); and (4) AGE-induced pathogenic responses were all attenuated by pre-application of AGE receptor antagonist FPS-ZM1 (20?µM) or the antioxidant glutathione precursor N-acetylcysteine (5?mM). Therefore, AGEs-treated murine ECTs recapitulate the key features of DCM's functional, cellular and molecular pathogenesis, and may serve as a robust in vitro model to investigate cellular structure-function relationships, signaling pathways relevant to DCM and pharmaceutical intervention strategies.
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