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Pubblicazioni recenti - diabetic cardiomyopathy
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Expression signature of miRNAs and the potential role of miR-195-5p in high-glucose-treated rat cardiomyocytes.
J Biochem Mol Toxicol2019 Nov;():e22423. doi: 10.1002/jbt.22423.
Shi Yuanqi, Yan Caichuan, Li Yang, Zhang Yuhao, Zhang Guocui, Li Mingzhu, Li Baoxin, Zhao Xin,
Abstract
MicroRNAs are endogenous small noncoding RNAs that posttranscriptionally regulate the expression of target genes and play crucial roles in diverse physiopathologic processes. In the current study, we examined the microRNA (miRNA) expression profile of high-glucose-treated neonatal rat cardiomyocytes and the potential mechanisms. Differentially expressed miRNAs were analyzed by a miRNA microarray and validated by a quantitative real-time polymerase chain reaction in high-glucose-treated rat cardiomyocytes. Based on the results of our previous study and the bioinformatics prediction, we identified miR-195-5p/SGK1/Nedd4-2/hERG as the top-ranked signal pathway in diabetes cell model in vitro. In summary, our present study provides novel insights into the regulatory mechanism of miR-195-5p/SGK1/Nedd4-2/hERG in rat cardiomyocytes under high-glucose stress, which may provide a novel idea for the development of diagnostic and therapeutic strategies for diabetic cardiomyopathy in the future.
© 2019 Wiley Periodicals, Inc.
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Lessons from the Trials for the Desirable Effects of Sodium Glucose Co-Transporter 2 Inhibitors on Diabetic Cardiovascular Events and Renal Dysfunction.
Int J Mol Sci2019 Nov;20(22):. doi: E5668.
Wakisaka Masanori, Kamouchi Masahiro, Kitazono Takanari,
Abstract
Recent large placebo-controlled trials of sodium glucose co-transporter 2 (SGLT2) inhibitors revealed desirable effects on heart failure (HF) and renal dysfunction; however, the mechanisms underlying these effects are unknown. The characteristic changes in the early stage of diabetic cardiomyopathy (DCM) are myocardial and interstitial fibrosis, resulting in diastolic and subsequent systolic dysfunction, which leads to clinical HF. Pericytes are considered to play crucial roles in myocardial and interstitial fibrosis. In both DCM and diabetic retinopathy (DR), microaneurysm formation and a decrease in capillaries occur, triggered by pericyte loss. Furthermore, tubulointerstitial fibrosis develops in early diabetic nephropathy (DN), in which pericytes and mesangial cells are thought to play important roles. Previous reports indicate that pericytes and mesangial cells play key roles in the pathogenesis of DCM, DR and DN. SGLT2 is reported to be functionally expressed in pericytes and mesangial cells, and excessive glucose and Na entry through SGLT2 causes cellular dysfunction in a diabetic state. Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature.
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Effects and mechanisms of PSS-loaded nanoparticles on coronary microcirculation dysfunction in streptozotocin-induced diabetic cardiomyopathy rats.
Biomed Pharmacother2019 Nov;121():109280. doi: S0753-3322(19)30813-3.
Mao Yongjun, Hu Yi, Feng Wenjing, Yu Luyan, Li Pengli, Cai Bing, Li Chunxia, Guan Huashi,
Abstract
Coronary microvascular dysfunction (CMD) is the pathological basis and pathogenesis of diabetic cardiomyopathy (DCM). Propylene glycol alginate sodium sulfate (PSS) as heparinoid drug has many biological activities. Here, a novel PSS-loaded nanoparticle (PSS-NP) was prepared to study its effect on the CMD of DCM. We used diabetes mellitus rat induced by STZ to establish the CMD model of DCM, and the study was detected by echocardiography, histological analysis, transmission electron microscopy, immunofluorescence staining, enzyme-linked immunosorbent assay, real time-PCR analysis, liquid-chip analysis, western blot analysis and so on. The experimental results suggested that PSS-NP could improve the survival state of rats, cardiac function, myocardial morphology and coronary microcirculation structure disorders, and increase the number of microvessels. In addition, we demonstrated that PSS-NP could alleviate the CMD by improving endothelial function, anticoagulation and antioxidative stress. The outcomes of this study provided new treatment thoughts for the therapy of coronary microcirculation dysfunction in DCM.
Copyright © 2019. Published by Elsevier Masson SAS.
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Astragaloside-IV protects H9C2(2-1) cardiomyocytes from high glucose-induced injury via miR-34a-mediated autophagy pathway.
Artif Cells Nanomed Biotechnol2019 Dec;47(1):4172-4181. doi: 10.1080/21691401.2019.1687492.
Zhu Yaobin, Qian Xin, Li Jingjing, Lin Xing, Luo Jiewei, Huang Jianbin, Jin Zhao,
Abstract
Diabetic cardiomyopathy (DCM) is an important cardiac disorder in patients with diabetes. High glucose (HG) levels lead to inflammation of cardiomyocytes, oxidative stress, and long-term activation of autophagy, resulting in myocardial fibrosis and remodelling. Astragaloside-IV (AS-IV) has a wide range of pharmacological effects. This study aimed to investigate the effects of AS-IV on injury induced by HG in rat cardiomyocytes (H9C2(2-1)) and the involvement of the miR-34a-mediated autophagy pathway. An AS-IV concentration of 100??M was selected based on H9C2(2-1) cell viability using the cell counting kit-8 (CCK-8). We found that 33?mM HG induced a morphologic change in cells and caused excessive oxidative stress, whereas AS-IV inhibited lipid peroxidation and increased superoxide dismutase activity. In terms of mRNA expression, HG increased miR-34a and inhibited Bcl2 and Sirt1, whereas AS-IV and miR-34a-inhibitor reversed the above effects. Further, LC3-GFP adenovirus infection and western blotting showed that HG increased autophagy, which was reversed synergistically by AS-IV and miR-34a-inhibitor. Bcl2 and pAKT/AKT protein expressions in the HG group was significantly lower than that in controls, but AS-IV and miR-34a-inhibitor antagonized the process. Thus, AS-IV inhibits HG-induced oxidative stress and autophagy and protects cardiomyocytes from injury via the miR-34a/Bcl2/(LC3II/LC3I) and pAKT/Bcl2/(LC3II/LC3I) pathways.
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Inhibition of microRNA-150-5p alleviates cardiac inflammation and fibrosis via targeting Smad7 in high glucose-treated cardiac fibroblasts.
J Cell Physiol2019 Nov;():. doi: 10.1002/jcp.29386.
Che Hui, Wang Yueqiu, Li Yang, Lv Jie, Li Hui, Liu Yining, Dong Ruixue, Sun Yongle, Xu Xiaodan, Zhao Jie, Wang Lihong,
Abstract
Hyperglycemia-induced cardiac fibrosis is a prominent characteristic of diabetic cardiomyopathy. Changes in proinflammatory cytokines have been shown to lead to cardiac fibrosis in patients with diabetes mellitus. This study aimed to investigate the role of miR-150-5p in mediating cardiac inflammation and fibrosis in cardiac fibroblasts (CFs). Herein, we found that high-glucose (HG) treatment significantly induced cardiac inflammation, as manifested by increased proinflammatory cytokine production (IL-1?) and NF-?B activity in CFs. Moreover, HG markedly aggravated cardiac fibrosis and increased levels of fibrotic markers (CTGF, FN, ?-SMA) and extracellular matrix proteins (Col-I, Col-III) in CFs. At the same time, HG disturbed the TGF-?1/Smad signaling pathway, as evidenced by increases in TGF-?1 and p-Smad2/3 levels and decreases in Smad7 levels in CFs. Furthermore, we found that miR-150-5p was upregulated by HG, which negatively regulated Smad7 expression at the posttranscription level. Further study demonstrated that cardiac inflammation and fibrosis in CFs were corrected following miR-150-5p knockdown, but exacerbated by miR-150-5p overexpression. These data indicated that miR-150-5p inhibition could ameliorate NF-?B-related inflammation and TGF-?1/Smad-induced cardiac fibrosis through targeting Smad7. Thus, miR-150-5p may be a novel promising target for treating diabetic cardiomyopathy.
© 2019 Wiley Periodicals, Inc.
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An Update on the Multifaceted Roles of STAT3 in the Heart.
Front Cardiovasc Med2019 ;6():150. doi: 10.3389/fcvm.2019.00150.
Harhous Zeina, Booz George W, Ovize Michel, Bidaux Gabriel, Kurdi Mazen,
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a signaling molecule and transcription factor that plays important protective roles in the heart. The protection mediated by STAT3 is attributed to its genomic actions as a transcription factor and other non-genomic roles targeting mitochondrial function and autophagy. As a transcription factor, STAT3 upregulates genes that are anti-oxidative, anti-apoptotic, and pro-angiogenic, but suppresses anti-inflammatory and anti-fibrotic genes. Its suppressive effects on gene expression are achieved through competing with other transcription factors or cofactors. STAT3 is also linked to the modification of mRNA expression profiles in cardiac cells by inhibiting or inducing miRNA. In addition to these genomic roles, STAT3 is suggested to function protectively in mitochondria, where it regulates ROS production, in part by regulating the activities of the electron transport chain complexes, although our recent evidence calls this role into question. Nonetheless, STAT3 is a key player known to be activated in the cardioprotective ischemic conditioning protocols. Through these varied roles, STAT3 participates in various mechanisms that contribute to cardioprotection against different heart pathologies, including myocardial infarction, hypertrophy, diabetic cardiomyopathy, and peripartum cardiomyopathy. Understanding how STAT3 is involved in the protective mechanisms against these different cardiac pathologies could lead to novel therapeutic strategies to treat them.
Copyright © 2019 Harhous, Booz, Ovize, Bidaux and Kurdi.
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Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function.
Metabolism2019 Nov;():154002. doi: S0026-0495(19)30217-3.
Sun Yike, Zhou Shanshan, Guo Hua, Zhang Jian, Ma Tianjiao, Zheng Yang, Zhang Zhiguo, Cai Lu,
Abstract
BACKGROUND:
AMP-activated protein kinase (AMPK), particularly AMPK?2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPK?2 gene (AMPK?2-KO) mice.
METHODS AND RESULTS:
T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPK?2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3?months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3?M). The rest continued normal diet or HFD until terminating study at the sixth month (6?M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3?M and 6?M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPK?2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3? pathway. However, these improving effects of SFN were abolished in AMPK?2-KO diabetic mice.
CONCLUSIONS:
AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3? signaling pathways.
Copyright © 2019. Published by Elsevier Inc.
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Astragaloside IV alleviates myocardial damage induced by type 2 diabetes via improving energy metabolism.
Mol Med Rep2019 Nov;20(5):4612-4622. doi: 10.3892/mmr.2019.10716.
Zhang Zhen, Wang Jing, Zhu Yingwei, Zhang Hui, Wang Hongxin,
Abstract
The aim of the present study was to evaluate the protective effect and mechanism of Astragaloside IV (ASIV) on myocardial injury induced by type 2 diabetes, with a focus on energy metabolism. Blood glucose, the hemodynamic index, left ventricular weight/heart weight (LVW/HW), the left ventricular systolic pressure (LVSP), the left ventricular end diastolic pressure (LVEDP) and cell survival rate were measured in streptozotocin?induced diabetes model rats. Western blot analysis, PCR, hematoxylin?eosin and TUNEL staining, flow cytometry and ELISA were used to detect: i) Cardiomyocyte damage indicators such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cytochrome c (Cyt C), caspase?3, cleaved caspase?3 and the apoptotic rate; ii) energy metabolism indicators such as ATP/AMP and ADP/AMP; and iii) energy metabolism associated pathway proteins such as peroxisome proliferator?activated receptor ? coactivator 1?? (PGC?1?) and nuclear respiratory factor 1 (NRF1). The present demonstrated increased blood glucose, LVW/HW, LVSP, LVEDP and the cardiomyocyte damage indicators (ANP, BNP, Cyt C and caspase?3), in the diabetic and high glucose?treated groups, which were decreased by ASIV. The expression of NRF?1 and PGC?1? significantly changed in the model group and was markedly improved following ASIV treatment. Furthermore, the abnormal energy metabolism in the model group was reversed by ASIV. According to the results, ASIV can regulate energy metabolism by regulating the release of PGC?1? and NRF1 to rescue the abnormal energy metabolism caused by diabetes mellitus, thus decreasing the myocardial damage caused by diabetic cardiomyopathy.
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SGLT1 Inhibition Boon or Bane for Diabetes Associated Cardiomyopathy.
Fundam Clin Pharmacol2019 Nov;():. doi: 10.1111/fcp.12516.
Kalra Jaspreet, Mangali Suresh Babu, Dasari Deepika, Bhat Audesh, Goel Srashti, Dhar Indu, Sriram Dharamrajan, Dhar Arti,
Abstract
Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent anti-diabetic agent which along with its anti-hyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes related cardiac perturbations.
© 2019 Société Française de Pharmacologie et de Thérapeutique.
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Protective Effects Of Astragalus Polysaccharides On Oxidative Stress In High Glucose-Induced Or SOD2-Silenced H9C2 Cells Based On PCR Array Analysis.
Diabetes Metab Syndr Obes2019 ;12():2209-2220. doi: 10.2147/DMSO.S228351.
Sun Qilin, Wu Xiaoyan, Wang Hao, Chen Wenjie, Zhao Xuelan, Yang Yehong, Chen Wei,
Abstract
Background:
Oxidative stress in cardiac myocytes is an important pathogenesis of diabetic cardiomyopathy (DCM). Previously, we reported that astragalus polysaccharide (APS) has protective effects against the oxidative stress of DCM. This study aimed to determine the effect of APS on the oxidative stress induced by hyperglycemia in H9C2 cells.
Methods:
Rat H9C2 cells were cultured in vitro and randomly divided into the control group, HG group, APS-HG group, siRNASOD2 group, and APS-siRNASOD2 group. The cellular ultrastructure was measured by transmission electron microscopy. Cell apoptosis was examined by TUNEL staining. Levels of reactive oxygen species (ROS) were detected by a quantitative fluorescence assay (DHE). 8-OH-dG and nitrotyrosine, the indicators of oxidative stress injury, were detected by immunohistochemistry. A PCR array was used to evaluate the expression levels of 84 oxidative stress genes in cultured cells, and the PCR array results were partially verified by Western blot.
Results:
APS treatment protected the H9C2 cell ultrastructure, reduced the level of cell apoptosis, inhibited cellular ROS production, and reduced the levels of oxidative stress injury indicators 8-OH-dG and nitrotyrosine in high glucose-induced or SOD2-silenced H9C2 cells. It also altered oxidative stress-related genes at the mRNA and protein levels.
Conclusion:
APS may improve antioxidant capacity and inhibit oxidative stress injury in high glucose induced H9C2 cells.
© 2019 Sun et al.
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Long noncoding RNA KCNQ1OT1 induces pyroptosis in diabetic corneal endothelial keratopathy
Am J Physiol Cell Physiol2019 11;():. doi: 10.1152/ajpcell.00053.2019.
Zhang Yanyan, Song Zhen, Li Xuran, Xu Shuo, Zhou Sujun, Jin Xin, Zhang Hong,
Abstract
Diabetic corneal endothelial keratopathy is an intractable ocular complication which seriously threaten vision. It has been suggested that diabetes is associated with pyroptosis, a type of inflammatory programmed cell death. Long noncoding RNA KCNQ1OT1 is involved in pathophysiological mechanisms of diabetic complications, including diabetic cardiomyopathy and diabetic retinopathy. The aim of this study was to investigate the mechanisms of KCNQ1OT1 in diabetic corneal endothelial keratopathy. Here, we reveal that KCNQ1OT1 and pyroptosis can be triggered in diabetic human and rats corneal endothelium, along with the high glucose-treated corneal endothelial cells. However, miR-214 expression was substantially decreased and in experiments with cultured cells. LDH assay verified pyroptosis in high glucose-treated cells. Bioinformatics prediction and luciferase assays showed that KCNQ1OT1 may bind miR-214 to regulate the expression of caspase-1. We further transfectec miR-214 mimic and inhibitor into the high glucose-treated corneal endothelial cells. The results showed that upregulation of miR-214 attenuated pyroptosis; conversely, knockdown of miR-214 promoted it. In addition, KCNQ1OT1 knockdown by a small interfering RNA decreased pyroptosis factors expressions, but enhanced miR-214 expression. To understand the mechanisms underlying the pre-pyroptotic properties of KCNQ1OT1, si-KCNQ1OT1 was co-transfected with or without miR-214 inhibitor. The results showed that pyroptosis was repressed after silencing KCNQ1OT1, but was reversed by co-transfection with miR-214 inhibitor, suggesting that KCNQ1OT1 mediated pyroptosis induced by high glucose via targeting miR-214. Therefore, the KCNQ1OT1/miR-214/caspase-1 signaling pathway represents a new mechanism of diabetic corneal endothelial keratopathy, and KCNQ1OT1 could potentially be a novel therapeutic target.
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Inhibition of miR-21 alleviated cardiac perivascular fibrosis via repressing EndMT in T1DM.
J Cell Mol Med2019 Nov;():. doi: 10.1111/jcmm.14800.
Li Qianqian, Yao Yufeng, Shi Shumei, Zhou Mengchen, Zhou Yingchao, Wang Mengru, Chiu Jeng-Jiann, Huang Zhengrong, Zhang Weili, Liu Min, Wang Qing, Tu Xin,
Abstract
In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial-mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR-21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up-regulated the mRNA level of miR-21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR-21 following with improving cardiac function and decreasing collagen deposition. miR-21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up-regulating SMAD7 whereas activating p-SMAD2 and p-SMAD3. In vitro, high glucose (HG) up-regulated miR-21 and induced EndMT in ECs, which was decreased by inhibition of miR-21. A highly conserved binding site of NF-?B located in miR-21 5'-UTR was identified. In ECs, SMAD7 is directly regulated by miR-21. In conclusion, the pathway of NF-?B/miR-21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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G protein-coupled receptor kinase-2: A potential biomarker for early diabetic cardiomyopathy.
J Diabetes2019 Oct;():. doi: 10.1111/1753-0407.12991.
Lai Shuiqing, Fu Xiaoying, Yang Shufen, Zhang Shuting, Lin Qiuxiong, Zhang Mengzhen, Chen Hongmei,
Abstract
BACKGROUND:
G protein-coupled receptor kinase-2 (GRK2) has been shown as a key regulator of cardiac function, and the myocardial GRK2 levels are mirrored by the levels in peripheral blood mononuclear cells (PBMCs). In this study, we evaluated the myocardial and PBMCs GRK2 levels in early diabetic cardiomyopathy (DCM).
METHODS:
C57BL/KS-db/db male diabetic mice at 12?weeks of age, as the type 2 diabetes (T2DM) animal model of early DCM were evaluated. Forty-four T2DM patients with left ventricular diastolic dysfunction (LVDD), without evidence of hypertension, coronary artery diseases, congestive heart failure, and diabetic complications and without evidence of ischemia in a maximal treadmill exercise test, were recruited as the DM?+?LVDD group; 30 age-matched T2DM patients without LVDD were recruited as the DM control group. Left ventricular diastolic function was evaluated by cardiac tissue Doppler. The pseudonormal pattern of ventricular filling and E'/A'?
RESULTS:
Compared to 8-week-old diabetic mice and 12-week-old control mice, GRK2-mRNA level and expression in myocardial tissues of 12-week-old diabetic mice were significantly increased, as well as the left ventricular wall thickness and systolic function. And the collagen volume fraction (CVF), collagen-3 expression, P53 expression, and cell apoptotic rate in the myocardium of 12-week-old diabetic mice elevated as well. The GRK2-mRNA level in PBMCs of DM with LVDD was significantly higher than in DM control without LVDD.
CONCLUSIONS:
GRK2 expression increased in the myocardial tissue and the PBMCs at the early stage of DCM. These data support further research on the role of GRK2 as the clinical biomarker for early DCM.
HIGHLIGHTS:
The GRK2 level elevated not only in the myocardium of diabetic mice with early stage of diabetic cardiomyopathy but also in the peripheral blood mononuclear cells of type 2 diabetic patients with the early stage of diabetic cardiomyopathy. The study findings suggested that the GRK2 was a potential biomarker for early diabetic cardiomyopathy.
© 2019 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
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The gut microbiota and diabetic cardiomyopathy in humans.
Diabetes Metab2019 Oct;():. doi: S1262-3636(19)30159-4.
Bastin M, Andreelli F,
Abstract
Type 2 diabetes (DT2) increases the risk of cardiovascular events and cardiac insufficiency. This insufficiency is mostly post-ischaemic in nature, but other aetiologies are possible in this high-risk population. In patients with DT2, diabetic cardiomyopathy is a recognized cause of cardiac insufficiency secondary to chronic hyperglycaemia and myocardial lipotoxicity, which promotes cardiomyocyte hypertrophy (and, frequently, apoptosis of these cells), interstitial fibrosis and a decrease in myocardial contractile performance. Several studies have shown that diabetic cardiomyopathy is associated with modifications to the intestinal microbiota, and changes in the synthesis of bacterial metabolites and their diffusion into the host, some of which appear to have direct deleterious effects on cardiac contractility. These findings open up new perspectives for pathophysiological studies by establishing the presence of a 'microbiota-myocardium' axis and raising the possibility of innovative new treatments. Correction of intestinal dysbiosis in patients with cardiac insufficiency could, therefore, constitute an innovative therapeutic approach to cases of this disease with a poor prognosis.
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
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Diabetes Mellitus Severity and a Switch From Using Lipoprotein Lipase to Adipose-Derived Fatty Acid Results in a Cardiac Metabolic Signature That Embraces Cell Death.
J Am Heart Assoc2019 Nov;8(21):e014022. doi: 10.1161/JAHA.119.014022.
Puri Karanjit, Lal Nathaniel, Shang Rui, Ghosh Sanjoy, Flibotte Stephane, Dyer Roger, Hussein Bahira, Rodrigues Brian,
Abstract
Background Fatty acid (FA) provision to the heart is from cardiomyocyte and adipose depots, plus lipoprotein lipase action. We tested how a graded reduction in insulin impacts the source of FA used by cardiomyocytes and the cardiac adaptations required to process these FA. Methods and Results Rats injected with 55 (D55) or 100 (D100) mg/kg streptozotocin were terminated after 4 days. Although D55 and D100 were equally hyperglycemic, D100 showed markedly lower pancreatic and plasma insulin and loss of lipoprotein lipase, which in D55 hearts had expanded. There was minimal change in plasma FA in D55. However, D100 exhibited a 2- to 3-fold increase in various saturated, monounsaturated, and polyunsaturated FA in the plasma. D100 demonstrated dramatic cardiac transcriptomic changes with 1574 genes differentially expressed compared with only 49 in D55. Augmented mitochondrial and peroxisomal ?-oxidation in D100 was not matched by elevated tricarboxylic acid or oxidative phosphorylation. With increasing FA, although control myocytes responded by augmenting basal respiration, this was minimized in D55 and reversed in D100. Metabolomic profiling identified significant lipid accumulation in D100 hearts, which also exhibited sizeable change in genes related to apoptosis and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. Conclusions With increasing severity of diabetes mellitus, when the diabetic heart is unable to control its own FA supply using lipoprotein lipase, it undergoes dramatic reprogramming that is linked to handling of excess FA that arise from adipose tissue. This transition results in a cardiac metabolic signature that embraces mitochondrial FA overload, oxidative stress, triglyceride storage, and cell death.
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The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart.
Cardiovasc Drugs Ther2019 Oct;():. doi: 10.1007/s10557-019-06914-9.
Tate Mitchel, Higgins Gavin C, De Blasio Miles J, Lindblom Runa, Prakoso Darnel, Deo Minh, Kiriazis Helen, Park Min, Baeza-Garza Carlos D, Caldwell Stuart T, Hartley Richard C, Krieg Thomas, Murphy Michael P, Coughlan Melinda T, Ritchie Rebecca H,
Abstract
PURPOSE:
Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy.
METHODS:
Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography.
RESULTS:
Akita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e'/a' ratio and E/e' ratio.
CONCLUSIONS:
Our findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.
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Genome-wide differential expression profiling of lncRNAs and mRNAs associated with early diabetic cardiomyopathy.
Sci Rep2019 Oct;9(1):15345. doi: 10.1038/s41598-019-51872-9.
Pant Tarun, Dhanasekaran Anuradha, Bai Xiaowen, Zhao Ming, Thorp Edward B, Forbess Joseph M, Bosnjak Zeljko J, Ge Zhi-Dong,
Abstract
Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes. There are no effective approaches to preventing its development in the clinic. Long noncoding RNAs (lncRNA) are increasingly recognized as important molecular players in cardiovascular disease. Herein we investigated the profiling of cardiac lncRNA and mRNA expression in type 2 diabetic db/db mice with and without early diabetic cardiomyopathy. We found that db/db mice developed cardiac hypertrophy with normal cardiac function at 6 weeks of age but with a decreased diastolic function at 20 weeks of age. LncRNA and mRNA transcripts were remarkably different in 20-week-old db/db mouse hearts compared with both nondiabetic and diabetic controls. Overall 1479 lncRNA transcripts and 1109 mRNA transcripts were aberrantly expressed in 6- and 20-week-old db/db hearts compared with nondiabetic controls. The lncRNA-mRNA co-expression network analysis revealed that 5 deregulated lncRNAs having maximum connections with differentially expressed mRNAs were BC038927, G730013B05Rik, 2700054A10Rik, AK089884, and Daw1. Bioinformatics analysis revealed that these 5 lncRNAs are closely associated with membrane depolarization, action potential conduction, contraction of cardiac myocytes, and actin filament-based movement of cardiac cells. This study profiles differently expressed lncRNAs in type 2 mice with and without early diabetic cardiomyopathy and identifies BC038927, G730013B05Rik, 2700054A10Rik, AK089884, and Daw1 as the core lncRNA with high significance in diabetic cardiomyopathy.
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IL-1? and Statin Treatment in Patients with Myocardial Infarction and Diabetic Cardiomyopathy.
J Clin Med2019 Oct;8(11):. doi: E1764.
Liberale Luca, Carbone Federico, Camici Giovanni G, Montecucco Fabrizio,
Abstract
Statins are effective lipid-lowering drugs with a good safety profile that have become, over the years, the first-line therapy for patients with dyslipidemia and a real cornerstone of cardiovascular (CV) preventive therapy. Thanks to both cholesterol-related and "pleiotropic" effects, statins have a beneficial impact against CV diseases. In particular, by reducing lipids and inflammation statins, they can influence the pathogenesis of both myocardial infarction and diabetic cardiomyopathy. Among inflammatory mediators involved in these diseases, interleukin (IL)-1? is a pro-inflammatory cytokine that recently been shown to be an effective target in secondary prevention of CV events. Statins are largely prescribed to patients with myocardial infarction and diabetes, but their effects on IL-1? synthesis and release remain to be fully characterized. Of interest, preliminary studies even report IL-1? secretion to rise after treatment with statins, with a potential impact on the inflammatory microenvironment and glycemic control. Here, we will summarize evidence of the role of statins in the prevention and treatment of myocardial infarction and diabetic cardiomyopathy. In accordance with the dual lipid-lowering and anti-inflammatory effect of these drugs and in light of the important results achieved by IL-1? inhibition through canakinumab in CV secondary prevention, we will dissect the current evidence linking statins with IL-1? and outline the possible benefits of a potential double treatment with statins and canakinumab.
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[Impact and related mechanism on the improvement of hyperglycemia-induced pyroptosis in H9c2 cells by mircoRNA-214].
Zhonghua Xin Xue Guan Bing Za Zhi2019 Oct;47(10):820-828. doi: 10.3760/cma.j.issn.0253-3758.2019.10.009.
Wang Y, Zhao R Z, Chen P K, Xu G X, Liu Z J, Long X P, Qiu Z M, Shi B,
Abstract
To investigate whether microRNA(miR)-214 can improve hyperglycemia induced pyroptosis in H9c2 cells through targeting caspase-1. H9c2 cells of rats those in good growth condition were selected and incubated into the T25 culture bottle after digestion and passage. Cells were cultured in an incubator at 37 ? with 5%CO(2), repeat passage was made after cell density reached about 80%, The 5(th) to 8(th) generations of cells were selected for the subsequent experiments. To observe the effect of overexpression of miR-214 on pyroptosis and caspase-1 expression in H9c2 cells induced by hyperglycemia, the cells were divided into 4 groups: Control group(H9c2 cells cultured normally), Hyperglycemia group (HG group, 50 mmol/L glucose was used to intervene H9c2 cells for 24 hours), miR-214 mimics+hyperglycosis group (mimics+HG group, H9c2 cells were transfected with miR-214 mimics for 24 hours and then treated with 50 mmol/L hyperglycosis for 24 hours), miR-214 mimic-negative control+hyperglycaemic group(MNC+HG group, H9c2 cells were transfected with miR-214 mimic-negative control for 24 hours and then treated with 50 mmol/L hyperglycaemic for 24 hours). In order to further verify the anti-pyroptosis effect of miR-214 was mediated by targeted inhibition on caspase-1, cells overexpressing caspase-1 were used in the rescue experiment. The cells overexpressing caspase-1 were divided into 4 groups: Hyperglycemia group (HG group, 50 mmol/L glucose was used to intervene H9c2 cells for 24 hours), miR-214 mimics+hyperglycosis group (mimics+HG group, H9c2 cells were transfected with miR-214 mimics for 24 hours and then treated with 50 mmol/L hyperglycosis for 24 hours), miR-214 mimics+hyperglycosis+recombinant adenovirus (Ad-caspase-1-EGFP) group with caspase-1 gene and EGFP green fluorescent protein expression (mimics+HG+Ad-caspase-1-EGFP group, H9c2 cells were transfected with caspase-1-green fluorescent protein-carrying adenovirus for 48 hours, followed by transfection of miR-214 mimics for 24 hours, and then treated with 50 mmol/L hyperglycaemia for 24 hours), miR-214 mimics+HG+Ad-EGFP empty virus group (mimics+HG+Ad-EGFP group, H9c2 cells were transfected with empty adenovirus containing green fluorescent protein for 48 hours, followed by transfection with miR-214 mimics for 24 hours, and then treated with 50 mmol/L hyperglycosis for 24 hours). The mRNA expression levels of miRNA-214 and caspase-1 in cells were detected by real-time quantitative PCR. The expression and localization of caspase-1 protein were detected by immunofluorescence assay. Western blot was used to detect protein expression levels of procaspase-1, cleaved caspase-1, NLRP3 and ACS with ?-actin as internal reference. The secretion of IL-1? and IL-18 in cell culture medium was detected by ELISA. The correlation between miR-214 and caspase-1 was detected by double luciferase reporter gene. (1) The mRNA expression levels of miR-214 and caspase-1 in each group: the mRNA expressions of miR-214 in HG group and MNC+HG group were significantly lower than that in control group(0.05). The mRNA expression of miR-214 in mimics+HG group was significantly higher than that in control group (0.05). The mRNA expression levels of caspase-1 in HG group and MNC+HG group were significantly higher than that in control group(0.05). The mRNA expression level of caspase-1 in mimics+HG group was lower than that in control group(0.05). (2) The expression of caspase-1 in each group: the green fluorescence intensity in the control group was weak, which was strong in the HG group and MNC+HG group. The green fluorescence expression was weaker in mimics+HG group than in HG group. (3) ASC and NLRP3 protein expression levels in each group: ASC and NLRP3 protein expression levels in HG group and MNC+HG group were higher than those in control group(0.05). ASC and NLRP3 protein expression levels were significantly lower in mimics+HG group than in mimics+HG group (0.05). (4) The secretion of IL-1? and IL-18 in the cell culture medium of each group: the content of IL-1? and IL-18 in the cell culture medium of HG group and MNC+HG group was significantly higher than that of control group (0.05). The content of IL-1? and IL-18 in the cell culture medium of mimics+HG group was significantly lower than that of the HG group (0.05). (5) Correlation between miR-214 and caspase-1: miR-214 specifically binds to caspase-1 3 'UTR. Meanwhile, Western blot results showed that cleaved caspase-1 protein expression levels were significantly higher in both HG group and MNC+HG group than in control group (0.05). The levels of cleaved caspase-1 were significantly lower in mimics+HG group than in HG group (0.05). There was no significant difference in procaspase-1 expression among groups (0.05). (6) The expression levels of procaspase-1, cleaved caspase-1, ASC and NLRP3 in each group in rescue experiment: there was no significant difference in the expression of procaspase-1 in each group (0.05). Cleaved caspase-1, ASC and NLRP3 protein expressions were significantly lower in mimics+HG group than in HG group (0.05). However, cleaved caspase-1, ASC and NLRP3 protein expressions were significantly higher in mimics+HG+ Ad-caspase-1-EGFP group than in mimics+HG group (0.05). (7) The expression of IL-1? and IL-18 in rescue experiment: the secretions of IL-1? and IL-18 in the cell culture medium of the mimics+HG group were significantly lower than that of HG group (0.05), which were significantly higher in mimics+HG+Ad-caspase-1-EGFP group than in mimics+HG group (0.05). miR-214 can improve the hyperglycemia induced pyroptosis in H9c2 cells by targeted inhibition of the caspase-1.
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Knockdown of long non-coding RNA LUCAT1 reverses high glucose-induced cardiomyocyte injury via targeting CYP11B2.
Eur Rev Med Pharmacol Sci2019 Oct;23(19):8560-8565. doi: 19171.
Yin Y, Yang Z-F, Li X-H, Zhou L-Q, Zhang Y-J, Yang B,
Abstract
OBJECTIVE:
Diabetic cardiomyopathy (DCM) is one of the major complications in patients with diabetes mellitus. Recently, long noncoding RNAs (lncRNAs) have been well concerned for their roles in the progression of multiple diseases, including DCM. In this research, we aimed to explore the role of lncRNA LUCAT1 in cardiomyocyte injury and apoptosis induced by high glucose (HG) in vitro.
MATERIALS AND METHODS:
High glucose-induced (HG-induced) AC16 cardiomyocytes transfected with LUCAT1 shRNA were constructed. LUCAT1 expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Subsequently, cell proliferation and cell apoptosis were detected after LUCAT1 knockdown in HG-induced AC16 cells. Moreover, RT-qPCR and Western blot assay were performed to explore the potential underlying mechanism of LUCAT1 in DCM.
RESULTS:
The expression of LUCAT1 was significantly upregulated in HG-treated AC16 cardiomyocytes. Moreover, knockdown of LUCAT1 could reverse cardiomyocyte injury and apoptosis through downregulating CYP11B2.
CONCLUSIONS:
We first demonstrated that knockdown of LUCAT1 could reverse HG-induced cardiomyocyte injury by down-regulating CYP11B2. Our findings might offer a new direction for interpreting the mechanism of DCM development.
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