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Pubblicazioni recenti - diabetic cardiomyopathy
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Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF??B signalling pathway in diabetic cardiomyopathy rats.
Mol Med Rep2021 Mar;23(3):. doi: 10.3892/mmr.2021.11854.
Jin Qinyang, Zhu Qin, Wang Kai, Chen Mengli, Li Xinli,
Abstract
Allisartan isoproxil is a new nonpeptide angiotensin II receptor blocker (ARB) precursor drug that is used to treat hypertension and reduce the risk of heart disease. The present study explored the effects of allisartan isoproxil on diabetic cardiomyopathy (DCM) and revealed the roles of hyperglycaemia?induced oxidative stress and inflammation. A rat DCM model was established by high?fat diet feeding in combination with intraperitoneal injection of streptozocin. Echocardiographs showed that diabetic rats exhibited significantly decreased cardiac function. Troponin T (cTnT) and B?type natriuretic peptide (BNP) were significantly increased in DCM rats as obtained by ELISA. Allisartan isoproxil significantly improved the EF% and E'/A' ratio. Histopathologic staining showed that allisartan isoproxil prevented histological alterations, attenuated the accumulation of collagen, and ameliorated cTnT and BNP levels. Western blot and immunohistochemical results indicated that the expression levels of silent information regulator 2 homologue 1 (SIRT1) and nuclear factor erythroid 2?related factor 2 (Nrf2) were decreased in the hearts of diabetic rats, and antioxidant defences were also decreased. In addition, allisartan isoproxil decreased the expression of NF??B p65 and the inflammatory cytokines TNF?? and IL?1? which were determined by reverse transcription?quantitative PCR in the diabetic heart. Western blotting and TUNEL staining results also showed that cardiac Bax and cleaved caspase?3 and the number of apoptotic myocardial cells were increased in the diabetic heart and decreased following treatment with allisartan isoproxil. In conclusion, the present results indicated that allisartan isoproxil alleviated DCM by attenuating diabetes?induced oxidative stress and inflammation through the SIRT1/Nrf2/NF??B signalling pathway.
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BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes.
Circ Res2021 Jan;():. doi: 10.1161/CIRCRESAHA.120.316656.
Carnicer Hijazo Ricardo, Duglan Drew, Ziberna Klemen, Recalde Alice, Reilly Svetlana, Simon Jillian N, Mafrici Simona, Arya Ritu, Roselló-Lletí Esther, Chuaiphichai Surawee, Tyler Damian J, Lygate Craig A, Channon Keith M, Casadei Barbara,
Abstract
In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the nitric oxide synthase (NOS) co-factor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype. Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes. In contrast to the vascular endothelium, BH4 levels, superoxide production and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca2+]i decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild type mice (WT) 12 weeks post-DM induction (streptozotocin, 42-45mg/kg) was prevented in mice with elevated myocardial BH4 content secondary to overexpression of GTP-cyclohydrolase 1 (mGCH1-Tg) and reversed in WT mice receiving oral BH4 supplementation from the 12th to the 18th week after DM induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of neuronal NOS (nNOS) in mGCH1-Tg. In HEK cells, S-nitrosoglutathione led to a PKG-dependent increase in plasmalemmal density of the insulin-independent glucose transporter, GLUT-1. In cardiomyocytes, mGCH1 overexpression induced a NO/sGC/PKG-dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31P MRS) and myocardial function. We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via a nNOS-mediated increase in non-insulin dependent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4-based therapeutics in human diabetic cardiomyopathy.
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Ophiopogonin D Alleviates Diabetic Myocardial Injuries by Regulating Mitochondrial Dynamics.
J Ethnopharmacol2021 Jan;():113853. doi: S0378-8741(21)00079-9.
Li Weiwei, Ji Louyin, Tian Jing, Tang Wenzhu, Shan Xiaoli, Zhao Pei, Chen Huihua, Zhang Chen, Xu Ming, Lu Rong, Guo Wei,
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Ophiopogonin D (OP-D) is a steroidal saponin extracted from Ophiopogon japonicus (Thunb.) Ker Gawl. (Liliaceae), that has been traditionally used to treat cough, sputum, and thirst in some Asian countries. Recently, various pharmacological roles of OP-D have been identified, including anti-inflammatory, cardioprotective, and anti-cancer effects. However, whether OP-D can prevent diabetic myocardial injury remains unknown.
AIM OF THE STUDY:
In this study, we aimed to observe the effects of OP-D on the diabetic myocardium.
MATERIALS AND METHODS:
Leptin receptor-deficient db/db mice were used as an animal model for type 2 diabetes. The effects of OP-D on blood glucose, blood lipids, myocardial ultrastructure, and mitochondrial function in mice were observed after four weeks of intragastric administration. Palmitic acid was used to stimulate cardiomyocytes to establish a myocardial lipotoxicity model. Cell apoptosis, mitochondrial morphology, and function were observed.
RESULTS:
Blood glucose and blood lipid levels were significantly increased in db/db mice, accompanied by myocardial mitochondrial injury and dysfunction. OP-D treatment reduced blood lipid levels in db/db mice and relieved mitochondrial injury and dysfunction. OP-D inhibited palmitic acid induced-mitochondrial fission and dysfunction, reduced endogenous apoptosis, and improved cell survival rate in H9C2 cardiomyocytes. Both in vivo and in vitro models showed increased phosphorylation of DRP1 at Ser-616, reduced phosphorylation of DRP1 at Ser-637, and reduced expression of fusion proteins MFN1/2 and OPA1. Meanwhile, immunofluorescence co-localization analysis revealed that palmitic acid stimulated the translocation of DRP1 protein from the cytoplasm to the mitochondria in H9C2 cardiomyocytes. The imbalance of mitochondrial dynamics, protein expression, and translocation of DRP1 were effectively reversed by OP-D treatment. In isolated mice ventricular myocytes, palmitic acid enhanced cytoplasmic Ca levels and suppressed contractility in ventricular myocytes, accompanied by activation of calcineurin, a key regulator of DRP1 dephosphorylation at Ser-637. OP-D reversed the changes caused by palmitic acid.
CONCLUSIONS:
Our findings indicate that OP-D intervention could alleviate lipid accumulation and mitochondrial injury in diabetic mouse hearts and palmitic acid-stimulated cardiomyocytes. The cardioprotective effect of OP-D may be mediated by the regulation of mitochondrial dynamics.
Copyright © 2021. Published by Elsevier B.V.
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Physiological And Pathological Roles Of Protein Kinase A In The Heart.
Cardiovasc Res2021 Jan;():. doi: cvab008.
Liu Yuening, Chen Jingrui, Fontes Shayne K, Bautista Erika N, Cheng Zhaokang,
Abstract
Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind ?-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signaling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions please email: journals.permissions@oup.com.
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The role of alpha-lipoic acid supplementation in the prevention of diabetes complications: A comprehensive review of clinical trials.
Curr Diabetes Rev2021 Jan;():. doi: 10.2174/1573399817666210118145550.
Jeffrey Sarah, Samraj Punitha Isaac, Raj Behin Sundara,
Abstract
Alpha-lipoic acid (ALA) is a substantial antioxidant in the prevention of diabetes and diabetes complications. It can regenerate other antioxidants like vitamin E, vitamin C, Coenzyme Q10 and glutathione and is often known as a universal antioxidant. Antioxidants play a role in diabetes treatment due to hyperglycemia-induced stimulation of the polyol pathway and formation of advanced glycation end products (AGE) and reactive oxygen species (ROS). Clinical trials examining alpha-lipoic acid supplementation on diabetic neuropathy, nephropathy, cardiomyopathy and erectile dysfunction display positive results, particularly in pain amelioration in neuropathy, asymmetric dimethylarginine reductions in nephropathy and improved oscillatory potential and contrast sensitivity in retinopathy. In diabetic cardiomyopathy (DCM), ALA offers protection through inhibition of NF-kB activation, reduction of fas-ligand and decrease in matrix metalloproteinase-2. This comprehensive review summarises and provides an understanding of the importance of alpha-lipoic acid supplementation to prevent diabetes complications.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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Metformin ameliorates ROS-p53-collagen axis of fibrosis and dyslipidemia in type 2 diabetes mellitus-induced left ventricular injury.
Arch Physiol Biochem2021 Jan;():1-7. doi: 10.1080/13813455.2020.1869265.
Al-Ani Bahjat, Alzamil Norah M, Hewett Peter W, Al-Hashem Fahaid, Bin-Jaliah Ismaeel, Shatoor Abdullah S, Kamar Samaa S, Latif Noha S Abdel, Haidara Mohamed A, Dawood Amal F,
Abstract
BACKGROUND:
The link between oxidative stress (ROS), apoptosis (p53) and fibrosis (collagen) in type 2 diabetes mellitus (T2DM)-induced cardiac injury in the presence and absence of the antidiabetic drug, metformin has not been investigated before.
MATERIAL AND METHODS:
T2DM was induced in rats by a combination of high carbohydrate and fat diets (HCFD) and streptozotocin (50?mg/kg) injection. The protection group started metformin (200?mg/kg) treatment 14?days prior to the induction of diabetes and continued on metformin and HCFD until being sacrificed at week 12.
RESULTS:
Diabetes significantly induced blood levels of ROS and left ventricular p53 and collagen expression that was inhibited by metformin. Metformin also significantly reduced glycated haemoglobin and dyslipidemia induced by diabetes. In addition, a significant correlation between ROS-p53-collagen axis and glycaemia and hyperlipidaemia was observed.
CONCLUSIONS:
These findings show that metformin provides substantial protection against diabetic cardiomyopathy-induced ROS-p53 mediated fibrosis and dyslipidemia.
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Subcellular microRNAs in diabetic cardiomyopathy.
Ann Transl Med2020 Dec;8(23):1602. doi: 10.21037/atm-20-2205.
Li Huaping, Fan Jiahui, Chen Chen, Wang Dao Wen,
Abstract
Cardiovascular complications are the leading causes of diabetes-related morbidity and mortality. The high incidence and poor prognosis of heart failure in diabetic patients have been associated, in part, to the presence of an underlying cardiomyopathy characterized by cardiac hypertrophy, cardiomyocytes apoptosis, and ?brosis. It has been unclear about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. Micro(mi)RNAs represent a class of small, 18- to 28-nucleotide-long, non-coding RNA molecules. MiRNAs typically suppress gene expression at the post-transcriptional levels by binding directly to the 3'-UTR of the target mRNAs in the cytoplasm. Interestingly, recent studies suggest that miRNAs may also regulate gene expression in a positive manner. Our recent studies have shown that subcellular miRNAs, such as cytosol-, mitochondria- and nucleus-localized miRNAs, were dramatically dysregulated in diabetic cardiomyopathy. Specifically, cytoplasm localized miRNAs regulate genes expression in a post-transcriptional manner. Nuclear localized miRNAs regulate gene transcription or chromosomal reconstruction through the non-canonical mechanism. Mitochondrial miRNAs stimulate, rather than repress, the translation of specific mitochondrial genome-encoded transcripts. By reviewing these latest discovered functions of subcellular miRNAs in diabetic animal models, we identified new mechanistic insights for diabetic cardiomyopathy. Understanding the nature of subcellular miRNAs will provide new therapeutic targets against diabetes-associated cardiac complications in the near future.
2020 Annals of Translational Medicine. All rights reserved.
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Cardiovascular disease in patients with COVID-19: evidence from cardiovascular pathology to treatment.
Acta Biochim Biophys Sin (Shanghai)2021 Jan;():. doi: gmaa176.
Luo Jinwen, Zhu Xiao, Jian Jie, Chen X U, Yin Kai,
Abstract
The coronavirus disease-2019 (COVID-19) caused by the novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly developed into a global pneumonia pandemic. At present, COVID-19 has caused more than 70,000,000 confirmed cases with over 1,500,000 deaths worldwide, as reported by WHO. Cardiovascular disease is the major comorbidity of COVID-19 patients and is closely related to the severity of COVID-19. SARS-CoV-2 infection can directly or indirectly cause a series of cardiac complications, including acute myocardial injury and myocarditis, heart failure and cardiac arrest, arrhythmia, acute myocardial infarction, cardiogenic shock, Takotsubo cardiomyopathy, and coagulation abnormalities. Intensive research on the SARS-CoV-2-associated cardiovascular complications is urgently needed to elucidate its exact mechanism and to identify potential drug targets, which will help to formulate effective prevention and treatment strategies. Hence, this review will summarize recent progress regarding the effects of COVID-19 on the cardiovascular system and describe the underlying mechanism of cardiovascular injury caused by SARS-CoV-2.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Diabetic cardiomyopathy and inflammation: development of hostile microenvironment resulting in cardiac damage.
Minerva Cardioangiol2021 Jan;():. doi: 10.23736/S0026-4725.20.05454-7.
Elia Edoardo, Ministrini Stefano, Carbone Federico, Montecucco Fabrizio,
Abstract
Diabetes mellitus is emerging as a major risk factor for heart failure. Diabetic cardiomyopathy is defined as a myocardial dysfunction that is not caused by underlying hypertension or coronary artery disease. Studies about clinical features, natural history and outcomes of the disease are few and often conflicting, because a universally accepted operative definition of diabetic cardiomyopathy is still lacking. Hyperglycemia and related metabolic and endocrine disorders are the triggering factors of myocardial damage in diabetic cardiomyopathy through multiple mechanisms. Among these mechanisms, inflammation has a relevant role, similar to other chronic myocardial disease, such as hypertensive or ischemic heart disease. A balance between inflammatory damage and healing processes is fundamental for homeostasis of myocardial tissue, whereas diabetes mellitus produces an imbalance, promoting inflammation and delaying healing. Therefore, diabetes-related chronic inflammatory state can produce a progressive qualitative deterioration of myocardial tissue, which reflects on progressive left ventricular functional impairment, which can be either diastolic, with prevalent myocardial hypertrophy, or systolic, with prevalent myocardial fibrosis. The aim of this narrative review is to summarize the existing evidence about the role of inflammation in diabetic cardiomyopathy onset and development. Ultimately, potential pharmacological strategies targeting inflammatory response will be reviewed and discussed.
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Salidroside protects against cardiomyocyte apoptosis and ventricular remodeling by AKT/HO-1 signaling pathways in a diabetic cardiomyopathy mouse model.
Phytomedicine2020 Nov;82():153406. doi: S0944-7113(20)30237-3.
Ni Jing, Li Yuanmin, Xu Yawei, Guo Rong,
Abstract
BACKGROUND:
Diabetic cardiomyopathy is characterized by both systolic and diastolic dysfunction due to decreased contractility, as well as reduced compliance of the myocardium. Oxidative stress plays a significant role in diabetes mellitus and its cardiovascular complications. Salidroside, a glucoside of the phenylpropanoid tyrosol, reportedly increases the levels of the antioxidative enzymes, nuclear factor erythroid 2-related factor 2, and heme oxygenase-1 (HO-1) to counteract oxidative stress; however, the underlying mechanisms are poorly understood.
PURPOSE:
Here we investigate the potential cardio-protective effects of salidroside and its mechanism in a diabetic animal model.
METHODS:
Male db/m, db/db, and age-matched wild-type mice were treated with salidroside at low dose (0.025 mg/kg) or high dose (0.05 mg/kg) by gavage every day for 12 weeks. Cardiac function and structure were assessed by echocardiography and histopathological examination. H9C2 cardiomyocytes were exposed in vitro to advanced glycosylation end products (400 ?g/ml) and treated with salidroside (0.1, 1, or 10 ?M). The expression of signaling-related genes were explored by western blotting and real-time PCR.
RESULTS:
Salidroside treatment significantly improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis in vivo. Mechanistically, salidroside markedly up-regulates HO-1 expression by activation of the AKT signaling pathway.
CONCLUSION:
Salidroside protects against cardiomyocyte apoptosis and ventricular remodeling in diabetic mice. This cardio-protective effect of salidroside is dependent on AKT signaling activation.
Copyright © 2020 Elsevier GmbH. All rights reserved.
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The effect of miR-471-3p on macrophage polarization in the development of diabetic cardiomyopathy.
Life Sci2021 Jan;268():118989. doi: S0024-3205(20)31749-5.
Liu Guangqi, Yan Dan, Yang Liu, Sun Yunwei, Zhan Lin, Lu Lili, Jin Zhigang, Zhang Chunxiang, Long Ping, Chen Jinhua, Yuan Qiong,
Abstract
AIMS:
The imbalance of M1/M2 macrophage ratio promotes the occurrence of diabetic cardiomyopathy (DCM), but the precise mechanisms are not fully understood. The aim of this study was to investigate whether miR-471-3p/silent information regulator 1 (SIRT1) pathway is involved in the macrophage polarization during the development of DCM.
METHODS:
Immunohistochemical staining was used to detect M1 and M2 macrophages infiltration in the heart tissue. Flow cytometry was used to detect the proportion of M1 and M2 macrophages. Expression of miR-471-3p was quantified by real time quantitative-PCR. Transfection of miRNA inhibitor into RAW264.7 cells was performed to investigate the underlying mechanisms. Bioinformatics methods and western blotting were used to explore the target gene of miR-471-3p and further confirmed by dual luciferase reporter assay.
KEY FINDINGS:
We observed that M1 macrophages infiltration in the heart of tissue in DCM while M2 type was decreased. M1/M2 ratio was increased significantly in bone marrow-derived macrophages (BMDMs) from db/db mice and in RAW264.7 cells treated with advanced glycation end products (AGEs). Meanwhile, miR-471-3p was significantly upregulated in RAW264.7 cells induced by AGEs and inhibition of miR-471-3p could reduce the inflammatory polarization of macrophages. Bioinformatics analysis identified SIRT1 as a target of miR-471-3p. Both dual luciferase reporter assay and western blotting verified that miR-471-3p negatively regulated SIRT1 expression. SIRT1 agonist resveratrol could downregulate the increased proportion of M1 macrophages induced by AGEs.
CONCLUSION:
Our results indicated that the development of DCM was related to AGEs-induced macrophage polarized to M1 type through a mechanism involving the miR-471-3p/SIRT1 pathway.
Copyright © 2021 Elsevier Inc. All rights reserved.
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Ultrasound-targeted microbubble destruction promotes myocardial angiogenesis and functional improvements in rat model of diabetic cardiomyopathy.
BMC Cardiovasc Disord2021 Jan;21(1):21. doi: 10.1186/s12872-020-01815-4.
Zhang Xijun, Tian Xinqiao, Li Peng, Zhu Haohui, Zhou Nanqian, Fang Zhixin, Yang Yuping, Jing Yun, Yuan Jianjun,
Abstract
BACKGROUND:
Microvascular insufficiency plays an important role in the development of diabetic cardiomyopathy (DCM), therapeutic angiogenesis has been mainly used for the treatment of ischemic diseases. This study sought to verify the preclinical performance of SonoVue microbubbles (MB) combined ultrasound (US) treatment on myocardial angiogenesis in the rat model of DCM and investigate the optimal ultrasonic parameters.
METHODS:
The male Sprague-Dawley (SD) rats were induced DCM by streptozotocin through intraperitoneal injecting and fed with high-fat diet. After the DCM model was established, the rats were divided into the normal group, DCM model group, and US?+?MB group, while the US?+?MB group was divided into four subsets according to different pulse lengths (PL) (8 cycles;18 cycle;26 cycle; 36 cycle). After all interventions, all rats underwent conventional echocardiography to examine the cardiac function. The rats were sacrificed and myocardial tissue was examined by histology and morphometry evaluations to detect the myocardial protective effect of SonoVue MBs using US techniques.
RESULTS:
From morphologic observation and echocardiography, the DCM rats had a series of structural abnormalities of cardiac myocardium compared to the normal rats. The US-MB groups exerted cardioprotective effect in DCM rats, improved reparative neovascularization and increased cardiac perfusion, while the 26 cycle group showed significant therapeutic effects on the cardiac functions in DCM rats.
CONCLUSION:
This strategy using SonoVue MB and US can improve the efficacy of angiogenesis, even reverse the progress of cardiac dysfunction and pathological abnormalities, especially using the 26 cycle parameters. Under further study, this combined strategy might provide a novel approach for early intervention of DCM in diabetic patients.
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The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes.
Pflugers Arch2021 Jan;():. doi: 10.1007/s00424-020-02505-y.
Hamilton Shanna, Veress Roland, Belevych Andriy, Terentyev Dmitry,
Abstract
Sudden cardiac death due to malignant ventricular arrhythmias remains the major cause of mortality in the postindustrial world. Defective intracellular Ca homeostasis has been well established as a key contributing factor to the enhanced propensity for arrhythmia in acquired cardiac disease, such as heart failure or diabetic cardiomyopathy. More recent advances provide a strong basis to the emerging view that hereditary cardiac arrhythmia syndromes are accompanied by maladaptive remodeling of Ca homeostasis which substantially increases arrhythmic risk. This brief review will focus on functional changes in elements of Ca handling machinery in cardiomyocytes that occur secondary to genetic mutations associated with catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome.
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Involvement of circHIPK3 in the pathogenesis of diabetic cardiomyopathy in mice.
Diabetologia2021 Jan;():. doi: 10.1007/s00125-020-05353-8.
Wang Wenjing, Zhang Shuchen, Xu Longjiang, Feng Yu, Wu Xiaoguang, Zhang Mengyao, Yu Zongliang, Zhou Xiang,
Abstract
AIMS/HYPOTHESIS:
In a mouse model of diabetic cardiomyopathy (DCM) the expression of the circular RNA circHIPK3 was found to be significantly increased. This study aimed to discover the molecular mechanisms linking circHIPK3 to the pathogenesis of DCM.
METHODS:
The diabetic mouse model was established by i.p. injection of streptozotocin, which led to the development of DCM. Echocardiographic measurements were used to evaluate cardiac structure and function, and histological staining was applied to detect myocardial fibrosis in mice. 5-Ethynyl-2'-deoxyuridine incorporation was performed to determine cell proliferation and RNA fluorescent in situ hybridisation was employed to examine circHIPK3 expression in cardiac fibroblasts. RNA immunoprecipitation and luciferase reporter assay were conducted to explore the pathological mechanism of circHIPK3 in myocardial fibrosis.
RESULTS:
Knockdown of circHIPK3 was found to attenuate myocardial fibrosis and enhance cardiac function in DCM mice. In addition, silencing of circHIPK3 could suppress proliferation of cardiac fibroblasts treated with angiotensin II. Furthermore, RNA immunoprecipitation and luciferase reporter assay revealed a circHIPK3-miR-29b-3p-Col1a1-Col3a1 regulatory network in the pathogenesis of myocardial fibrosis.
CONCLUSIONS/INTERPRETATION:
circHIPK3 contributes to increased myocardial fibrosis during DCM by functioning as a competing endogenous RNA that upregulates Col1a1 and Col3a1 expression through suppressing miR-29b-3p.
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Impact of peroxisome proliferator-activated receptor-? on diabetic cardiomyopathy.
Cardiovasc Diabetol2021 Jan;20(1):2. doi: 10.1186/s12933-020-01188-0.
Wang Lin, Cai Yin, Jian Liguo, Cheung Chi Wai, Zhang Liangqing, Xia Zhengyuan,
Abstract
The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor ? (PPAR?), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPAR? activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPAR? in association with the underlying pathophysiological changes in DCM. We discuss the PPAR?-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium-glucose co-transporter 2 inhibitor) in treating DCM.
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Polydatin and polydatin-loaded chitosan nanoparticles attenuate diabetic cardiomyopathy in rats.
J Mol Histol2021 Jan;():. doi: 10.1007/s10735-020-09930-4.
Mostafa Fatma, Abdel-Moneim Adel, Abdul-Hamid Manal, Galaly Sanaa R, Mohamed Hanaa M,
Abstract
Hyperglycemia is associated with impairment of heart function. The current study aimed to investigate the ameliorative effect of polydatin-loaded chitosan nanoparticles (PD-CSNPs), polydatin (PD) and metformin (MET) on diabetic cardiomyopathy in rats. Rats divided into six groups; normal-control, diabetic-control, diabetic + CSNPs (diabetic rats treated with 50 mg/kg blank chitosan nanoparticles), diabetic + PD-CSNPs (diabetic rats treated with PD-CSNPs equivalent to 50 mg/kg of polydatin), diabetic + PD (diabetic rats given 50 mg/kg polydatin), diabetic + MET (diabetic rats given 100 mg/kg metformin), orally and daily for 4 weeks. Treatment of diabetic rats with PD-CSNPs, PD and MET showed a significant reduction in the values of glucose and glycosylated hemoglobin with improvement in heart function biomarkers through decreasing serum creatine kinase and creatine kinase myocardial band activities compared to diabetic control. The treatment agents also suppressed the elevated lipid peroxidation product, increased values of glutathione content, superoxide dismutase, superoxide peroxidase, and catalase activities in the heart of diabetic treated rats. Furthermore, PD-CSNPs, PD and MET decreased heart tissue levels of a pro-inflammatory cytokine; tumor necrosis factor-alpha and nuclear factor-kappa ?, upregulation of heart gene expressions; nuclear factor erythroid 2-related factor 2 and heme oxygenase-1. Histological and ultrastructural examinations revealed the ameliorative effect of PD-CSNPs, PD and MET against the harmful of diabetic cardiomyopathy by reducing the cardiac fibers, necrotic cardiac myocytes, inflammatory cell infiltration, and the arrangement of the myofibrils and intercalated discs. In conclusion, the new formula of PD-CSNPs was more effective than PD and MET in amelioration the diabetic cardiomyopathy through its antioxidant, anti-inflammatory and prolonged-release properties.
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MiR-21-3p triggers cardiac fibroblasts pyroptosis in diabetic cardiac fibrosis via inhibiting androgen receptor.
Exp Cell Res2020 Dec;399(2):112464. doi: S0014-4827(20)30717-5.
Shi Peng, Zhao Xu-Dong, Shi Kai-Hu, Ding Xuan-Sheng, Tao Hui,
Abstract
AIMS/HYPOTHESIS:
MicroRNA-21 has been implicated in diabetic complication, including diabetic cardiomyopathy. However, there is limited information regarding the biological role of the miR-21 passenger strand (miR-21-3p) in diabetic cardiac fibrosis. The aim of this study was to investigate the role of miR-21-3p and its target androgen receptor in STZ-induced diabetic cardiac fibrosis.
METHODS:
The pathological changes and collagen depositions was analyzed by HE, Sirius Red staining and Masson's Trichrome Staining. MiR-21-3p, AR, NLRP3, caspase1 and collagen I expression were analyzed by western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, miR one step qRT-PCR, respectively. A luciferase reporter assay was used to verify the interaction between miR-21 and the 3' untranslated region (3'UTR) of AR.
RESULTS:
Our results indicated that miR-21-3p level was up-regulated, while AR was decreased in STZ-induced diabetic cardiac fibrosis tissues and cardiac fibroblast. High glucose triggers cardiac fibroblasts pyroptosis and collagen deposition. Gain-of-function and loss-of-function assays demonstrated that miR-21-3p mediated the crucial role in diabetic cardiac fibrosis. Our results show that miR-21-3p bound to the 3'UTR of AR post-transcriptionally repressed its expression. We also found AR, which regulates cardiac fibroblasts pyroptosis and collagen deposition through caspase1 signaling.
CONCLUSIONS:
/interpretation: Taken together, our study showed that miR-21-3p aggravates STZ-induced diabetic cardiac fibrosis through the caspase1 pathways by suppressing AR expression.
Copyright © 2020 Elsevier Inc. All rights reserved.
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Escitalopram Ameliorates Cardiomyopathy in Type 2 Diabetic Rats via Modulation of Receptor for Advanced Glycation End Products and Its Downstream Signaling Cascades.
Front Pharmacol2020 ;11():579206. doi: 10.3389/fphar.2020.579206.
Ahmed Lamiaa A, Shiha Nesma A, Attia Amina S,
Abstract
Type 2 diabetes mellitus (T2DM) has been recognized as a known risk factor for cardiovascular diseases. Additionally, studies have shown the prevalence of depression among people with diabetes. Thus, the current study aimed to investigate the possible beneficial effects of escitalopram, a selective serotonin reuptake inhibitor, on metabolic changes and cardiac complications in type 2 diabetic rats. Diabetes was induced by feeding the rats high fat-high fructose diet (HFFD) for 8 weeks followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg, i. p.). Treatment with escitalopram (10 mg/kg/day; p. o.) was then initiated for 4 weeks. At the end of the experiment, electrocardiography was performed and blood samples were collected for determination of glycemic and lipid profiles. Animals were then euthanized and heart samples were collected for biochemical and histopathological examinations. Escitalopram alleviated the HFFD/STZ-induced metabolic and cardiac derangements as evident by improvement of oxidative stress, inflammatory, fibrogenic and apoptotic markers in addition to hypertrophy and impaired conduction. These results could be secondary to its beneficial effects on the glycemic control and hence the reduction of receptor for advanced glycation end products content as revealed in the present study. In conclusion, escitalopram could be considered a favorable antidepressant medication in diabetic patients as it seems to positively impact the glycemic control in diabetes in addition to prevention of its associated cardiovascular complications.
Copyright © 2020 Ahmed, Shiha and Attia.
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Long noncoding RNA OIP5-AS1 overexpression promotes viability and inhibits high glucose-induced oxidative stress of cardiomyocytes by targeting microRNA-34a/SIRT1 axis in diabetic cardiomyopathy.
Endocr Metab Immune Disord Drug Targets2020 Dec;():. doi: 10.2174/1871530321666201230090742.
Sun Haiyun, Wang Chong, Zhou Ying, Cheng Xingbo,
Abstract
OBJECTIVE:
Diabetic cardiomyopathy (DCM) is an important complication of diabetes. This study was attempted to discover the effects of long noncoding RNA OIP5-AS1 (OIP5-AS1) on the viability and oxidative stress of cardiomyocyte in DCM.
METHODS:
The expression of OIP5-AS1 and microRNA-34a (miR-34a) in DCM was detected by qRT-PCR. In vitro, DCM was simulated by high glucose (HG, 30 mM) treatment in H9c2 cells. The viability of HG (30 mM)-treated H9c2 cells was examined by MTT assay. The reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA) levels were used to evaluate the oxidative stress of HG (30 mM)-treated H9c2 cells. Dual-luciferase reporter assay was used to confirm the interactions among OIP5-AS1, miR-34a and SIRT1. Western blot was applied to analyze the protein expression of SIRT1.
RESULTS:
The expression of OIP5-AS1 was down-regulated in DCM, but miR-34a was up-regulated. The functional experiment stated that OIP5-AS1 overexpression increased the viability and SOD level, while decreased the ROS and MDA levels in HG (30 mM)-treated H9c2 cells. The mechanical experiment confirmed that OIP5-AS1 and SIRT1 were both targeted by miR-34a with the complementary binding sites at 3'UTR. MiR-34a overexpression inhibited the protein expression of SIRT1. In the feedback experiments, miR-34a overexpression or SIRT1 inhibition weakened the promoting effect on viability, and mitigated the reduction effect on oxidative stress caused by OIP5-AS1 overexpression in HG (30 mM)-treated H9c2 cells.
CONCLUSIONS:
OIP5-AS1 overexpression enhanced viability and attenuated oxidative stress of cardiomyocyte via regulating miR-34a/SIRT1 axis in DCM, providing a new therapeutic target for DCM.
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Diabetic cardiomyopathy attenuated the protective effect of ischaemic post-conditioning against ischaemia-reperfusion injury in the isolated rat heart model.
Arch Physiol Biochem2020 Dec;():1-12. doi: 10.1080/13813455.2020.1866017.
Kurian Gino A, Ansari Mahalakshmi, Prem Priyanka N,
Abstract
The present study was designed to investigate the efficacy of post-conditioning (POC) in the diabetic heart with myopathy (DCM) against ischaemia-reperfusion (I/R) injury in an isolated rat heart model. Present work includes three groups of male Wistar rat viz., (i) normal, (ii) diabetes mellitus (DM) and (iii) DCM and each group was subdivided into normal perfusion, I/R, and POC. Isolated heart from the rats was analysed for tissue injury, contractile function, mitochondrial function, and oxidative stress. Results demonstrated that unlike in DM heart and normal heart, POC procedure failed to recover the DCM heart from I/R induced cardiac dysfunction (measured via cardiac hemodynamics and infarct size. POC was unsuccessful in preserving mitochondrial subsarcolemmal fraction during I/R when compared with DM and normal heart. To conclude, the development of myopathy in diabetic heart abolished the cardioprotective efficacy of POC and the underlying pathology was linked with the mitochondrial dysfunction. KEY MESSAGES Early studies reported contradicting response of diabetic heart towards post-conditioning mediated cardioprotection. Deteriorated mitochondrial function underlines the failure of post-conditioning in DCM. Efficacy of cardioprotection depends on the varying pathology of different diabetes stages.
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