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Pubblicazioni recenti - diabetic cardiomyopathy
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O-GlcNAc transferase affects the signal transduction of ?1 adrenoceptor in adult rat cardiomyocytes by increasing the O-GlcNAcylation of ?1 adrenoceptor.
Biochem Biophys Res Commun2020 May;():. doi: S0006-291X(20)30917-7.
Cao Hong, Hu Ying, Zhu Xiaofang, Yao Na, Gu Jiaona, Wang Yuhang, Zhu Weizhong,
Abstract
O-GlcNAcylation was first found by Torres and Hart in monocytes. It is a dynamic and reversible post-translational modification catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation is increased in diabetic cardiomyopathy (DCM) patients and it has been reported that OGT plays an important role in the regulation of cardiac gene transcription, cell cycle and calcium homeostasis. The purpose of this study is to investigate the effects of OGT on signal transduction and function of ?1-adrenoceptor (?1AR) in adult rat cardiomyocytes. We found that after overexpressing OGT by adenovirus vector in adult rat cardiomyocytes, cAMP formation and phosphorylation of phospholamban (PLB) at Ser16 (p16-PLB) were decreased under isoprenaline (ISO) stimulation. Over expression of OGT increased the intracellular [Ca]i and deteriorated the death of cardiomyocytes induced by prolonged stimulation with ISO. ?1-adrenoceptor was overexpressed using a plasmid vector and then co-immunoprecipitation (co-IP) followed by Western blot was employed to define the O-GlcNAcylation of ?1-adrenoceptor. The results showed that O-GlcNAcylation of ?1-adrenoceptor was increased in OGT overexpressed cells, and there was no significant change in the formation of cAMP and phosphorylation of PLB after ?1-adrenoceptor was blocked by CGP20712A. Given that OGT affects the signal transduction of ?1-adrenoceptor in adult rat cardiomyocytes by increasing the O-GlcNAcylation of ?1-adrenoceptor, the mechanism revealed in this study indicates that OGT and ?1AR may be therapeutic targets in patients undergoing diabetic cardiomyopathy.
Copyright © 2020 Elsevier Inc. All rights reserved.
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Metabolic syndrome and myocardium steatosis in subclinical type 2 diabetes mellitus: a H-magnetic resonance spectroscopy study.
Cardiovasc Diabetol2020 May;19(1):70. doi: 10.1186/s12933-020-01044-1.
Gao Yue, Ren Yan, Guo Ying-Kun, Liu Xi, Xie Lin-Jun, Jiang Li, Shen Meng-Ting, Deng Ming-Yan, Yang Zhi-Gang,
Abstract
BACKGROUND:
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that collectively cause an increased risk of type 2 diabetes mellitus (T2DM) and nonatherosclerotic cardiovascular disease. This study aimed to evaluate the role of myocardial steatosis in T2DM patients with or without MetS, as well as the relationship between subclinical left ventricular (LV) myocardial dysfunction and myocardial steatosis.
METHODS AND MATERIALS:
We recruited 53 T2DM patients and 20 healthy controls underwent cardiac magnetic resonance examination. All T2DM patients were subdivide into two group: MetS group and non-MetS. LV deformation, perfusion parameters and myocardial triglyceride (TG) content were measured and compared among these three groups. Pearson's and Spearman analysis were performed to investigate the correlation between LV cardiac parameters and myocardial steatosis. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between myocardial steatosis and LV subclinical myocardial dysfunction.
RESULTS:
An increase in myocardial TG content was found in the MetS group compared with that in the other groups (MetS vs. non-MetS: 1.54?±?0.63% vs. 1.16?±?0.45%; MetS vs. normal: 1.54?±?0.63% vs. 0.61?±?0.22%; all p?
CONCLUSION:
Myocardial TG content increased in T2DM patients with concurrent MetS. Myocardial steatosis was positively associated with decreased myocardial deformation and perfusion dysfunction, which may be an indicator for predicting diabetic cardiomyopathy.
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The Association of BMI and Diabetes Mellitus with Mortality in End Stage Heart Failure Patients on Inotropes.
J Heart Lung Transplant2020 Apr;39(4S):S235. doi: S1053-2498(20)30915-3.
Khan M A, Saadi T Al, Adhikari S, Hussain S, Asghar M, Kamba K, Soltys M, Morreale C, Glowacki N, Joshi A, Pauwaa S, Sciamanna C, Dia M, Macaluso G, Andrade A, Cotts W,
Abstract
PURPOSE:
Risk factors such as diabetes mellitus (DM) have been associated with increased risk of mortality in patients with heart failure (HF). Obesity in diabetic patients worsens outcomes. However, there appears to be an obesity paradox in which stable HF patients with higher body mass index (BMI) have better survival. We sought to evaluate the association of DM and BMI with mortality in patients with end stage HF on palliative inotropic therapy.
METHODS:
We performed a single center, retrospective chart review of HF patients who were placed on inotropes (milrinone or dobutamine) as palliative therapy from January 1, 2010 and followed up until October 1, 2019. Patients who received mechanical circulatory support or heart transplant were excluded. Patients were categorized by BMI (<25Kg/m 25-35Kg/m and >35Kg/m). The primary outcome was all cause mortality. Multivariate cox proportional hazard regression model was used for analysis.
RESULTS:
115 patients were included. Unadjusted analysis revealed significant relationship between mortality and coronary artery disease (HR 1.981; p value 0.01) and ischemic cardiomyopathy (HR 1.941; p value 0.01). After adjusting baseline characteristics using multivariate analysis (Table 1), mortality was associated with DM (p value 0.04) and history of CABG (p value 0.03). There was no significant association between mortality and BMI in either unadjusted or adjusted models. When entered as a continuous value, creatinine level (p value 0.02) was a predictor for mortality in both models.
CONCLUSION:
In patients with end stage HF on inotropic therapy, DM and worsening renal function are associated with increased mortality. BMI does not appear to affect mortality in these patients. Our small sample size was a significant limitation. More studies are needed to further characterize risk factors and help determine which patients would derive the most benefit from palliative inotropic therapy if they are not candidates, or do not desire advanced HF therapies.
Copyright © 2020. Published by Elsevier Inc.
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Multi-Omics Analysis of Diabetic Heart Disease in the Model Reveals Potential Targets for Treatment by a Longevity-Associated Gene.
Cells2020 May;9(5):. doi: E1283.
Faulkner Ashton, Dang Zexu, Avolio Elisa, Thomas Anita C, Batstone Thomas, Lloyd Gavin R, Weber Ralf Jm, Najdekr Luká?, Jankevics Andris, Dunn Warwick B, Spinetti Gaia, Vecchione Carmine, Puca Annibale A, Madeddu Paolo,
Abstract
Characterisation of animal models of diabetic cardiomyopathy may help unravel new molecular targets for therapy. Long-living individuals are protected from the adverse influence of diabetes on the heart, and the transfer of a longevity-associated variant (LAV) of the human gene protects cardiac function in the mouse model. This study aimed to determine the effect of therapy on the metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptome (next-generation RNAseq) in mice. UHPLC-MS showed that 493 cardiac metabolites were differentially modulated in diabetic compared with non-diabetic mice, mainly related to lipid metabolism. Moreover, only 3 out of 63 metabolites influenced by therapy in diabetic hearts showed a reversion from the diabetic towards the non-diabetic phenotype. RNAseq showed 60 genes were differentially expressed in hearts of diabetic and non-diabetic mice. The contrast between - and vehicle-treated diabetic hearts revealed eight genes differentially expressed, mainly associated with mitochondrial and metabolic function. Bioinformatic analysis indicated that re-programmed the heart transcriptome and metabolome rather than reverting it to a non-diabetic phenotype. Beside illustrating global metabolic and expressional changes in diabetic heart, our findings pinpoint subtle changes in mitochondrial-related proteins and lipid metabolism that could contribute to -induced cardio-protection in a murine model of type-2 diabetes.
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FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes.
J Cell Mol Med2020 May;():. doi: 10.1111/jcmm.15418.
Yan Dan, Cai Yin, Luo Jierong, Liu Jingjin, Li Xia, Ying Fan, Xie Xiang, Xu Aimin, Ma Xiaosong, Xia Zhengyuan,
Abstract
Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non-obese insulin-deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over-activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1-selective inhibitor AS1842856 was administered to streptozotocin-induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non-diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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Cardioprotective effects of melatonin: Focusing on its roles against diabetic cardiomyopathy.
Biomed Pharmacother2020 May;128():110260. doi: S0753-3322(20)30452-2.
Song Yan-Jun, Zhong Chong-Bin, Wu Wei,
Abstract
Melatonin is a pineal-produced indole known for its anti-aging, antiapoptotic and antioxidant properties. In past decades, the protective potentials of melatonin for cardiovascular diseases, such as atherosclerosis and myocardial infarction, have been widely revealed, triggering more investigations focused on other cardioprotective effects of melatonin. Recently, the roles of melatonin in diabetic cardiomyopathy (DCM) have attracted increased attention. In this regard, researchers found that melatonin attenuated cardiac fibrosis and hypertrophy, thus interrupting the development of DCM. Retinoid-related orphan receptor ? is a key melatonin receptor that contributed to the cardioprotective effect of melatonin in hearts with DCM. For the downstream mechanisms, the inhibition of mammalian STE20-like kinase 1 plays a pivotal role, which exerts antiapoptotic and proautophagic effects, thus enhancing cardiac tolerance in high-glucose conditions. In addition, other signalling mechanisms, such as sirtuin-1/peroxisome proliferator-activated receptor gamma-coactivator alpha and endoplasmic reticulum-related signalling, are also involved in the protective effects of melatonin on cardiomyocytes under diabetic conditions. This review will focus on the protective signalling mechanisms regulated by melatonin and provide a better understanding of the therapeutic applications of melatonin signalling in DCM.
Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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Emerging role of transcription factor EB in mitochondrial quality control.
Biomed Pharmacother2020 May;128():110272. doi: S0753-3322(20)30464-9.
Wang Shujun, Chen Yanse, Li Xiaoyu, Zhang Weihuang, Liu Zejian, Wu Man, Pan Qingjun, Liu Huafeng,
Abstract
Mitochondria are energy producers that play a vital role in cell survival. Mitochondrial dysfunction is involved in many diseases, including metabolic syndrome, neurodegenerative disorders, cardiomyopathies, cancer, obesity, and diabetic kidney disease, and challenges still remain in terms of treatments for these diseases. Mitochondrial quality control (MQC), which is defined as the maintenance of the quantity, morphology, and function of mitochondria, plays a pivotal role in maintaining cellular metabolic homeostasis and cell survival. Recently, growing evidence suggests that the transcription factor EB (TFEB) plays a pivotal role in MQC. Here, we systemically investigate the potential role and mechanisms of TFEB in MQC, which include the activation of mitophagy, regulation of mitochondrial biogenesis, reactive oxygen species (ROS) clearance, and the balance of mitochondria fission-fusion cycle. Importantly, we further discuss the therapeutic measures and effects aimed at TFEB on mitochondrial dysfunction-related diseases. Taken together, targeting TFEB to regulate MQC may represent an appealing therapeutic strategy for mitochondrial dysfunction related-diseases.
Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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From the gut to the heart: L. plantarum and inulin administration as a novel approach to control cardiac apoptosis via 5-HT2B and TrkB receptors in diabetes.
Clin Nutr2020 May;():. doi: S0261-5614(20)30220-X.
Sefidgari-Abrasi Safa, Roshangar Leila, Karimi Pouran, Morshedi Mohammad, Rahimiyan-Heravan Marziyeh, Saghafi-Asl Maryam,
Abstract
BACKGROUND & AIMS:
Type 2 diabetes mellitus, as a metabolic disorder, can lead to diabetic cardiomyopathy, identified by cardiomyocyte apoptosis and myocardial fibrosis. Brain-derived neurotrophic factor (BDNF) and serotonin are two neurotransmitters that can control cardiomyocyte apoptosis and myocardial fibrosis through their cardiac receptors. In the present study, we investigated the impacts of L. plantarum and inulin supplementation on the inhibition of cardiac apoptosis and fibrosis by modulating intestinal, serum, and cardiac levels of serotonin and BDNF as well as their cardiac receptors.
METHODS:
Diabetes was induced by a high-fat diet and streptozotocin in male Wistar rats. Rats were divided into six groups and were supplemented with L. plantarum, inulin or their combination for 8 weeks. Finally, the rats were killed and levels of intestinal, serum, and cardiac parameters were evaluated.
RESULTS:
Concurrent administration of L. plantarum and inulin caused a significant rise in the expression of cardiac serotonin and BDNF receptors (P < 0.001) as well as a significant fall in cardiac interstitial and perivascular fibrosis (P < 0.001, both) and apoptosis (P = 0.01). Moreover, there was a strong correlation of cardiac 5-Hydroxytryptamine 2B (5-HT2B) and tropomyosin receptor kinase B (TrkB) receptors with interstitial/perivascular fibrosis and apoptosis (P < 0.001, both).
CONCLUSIONS/INTERPRETATION:
Results revealed beneficial effects of L. plantarum, inulin or their combination on intestinal, serum, and cardiac serotonin and BDNF accompanied by higher expression of their cardiac receptors and lower levels of cardiac apoptotic and fibrotic markers. It seems that L. plantarum and inulin supplementation could be considered as a novel adjunct therapy to reduce cardiac complications of type 2 diabetes mellitus.
Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
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NADPH oxidase: A membrane-bound enzyme and its inhibitors in diabetic complications.
Eur J Pharmacol2020 May;():173206. doi: S0014-2999(20)30298-3.
Laddha Ankit P, Kulkarni Yogesh A,
Abstract
The human body has a mechanism for balancing the generation and neutralization of reactive oxygen species. The body is exposed to many agents that are responsible for the generation of reactive oxygen/nitrogen species, which leads to disruption of the balance between generation of these species and oxidative stress defence mechanisms. Diabetes is a chronic pathological condition associated with prolonged hyperglycaemia. Prolonged elevation of level of glucose in the blood leads to the generation of reactive oxygen species. This generation of reactive oxygen species is responsible for the development of diabetic vasculopathy, which includes micro- and macrovascular diabetic complications. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a membrane-bound enzyme responsible for the development of reactive oxygen species in hyperglycaemia. Phosphorylation of the cytosolic components of NOX, such as p47phox, p67phox, and RAC-1, in hyperglycaemia is one of the important causes of conversion of oxygen to reactive oxygen. Overexpression of NOX in pathological conditions is associated with activation of aldose reductase, advanced glycation end products, protein kinase C and the hexosamine pathway. In addition, NOX also promotes the activation of inflammatory cytokines, such as TGF-?, TNF-?, NF-k?, IL-6, and IL-18, the activation of endothelial growth factors, such as VEGF and FGF, hyperlipidaemia, and the deposition of collagen. Thus, overexpression of NOX is linked to the development of diabetic complications. The present review focuses on the role of NOX, its associated pathways, and various NOX inhibitors in the management and treatment of diabetic complications, such as diabetic nephropathy, retinopathy, neuropathy and cardiomyopathy.
Copyright © 2020. Published by Elsevier B.V.
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Basic Mechanisms of Diabetic Heart Disease.
Circ Res2020 May;126(11):1501-1525. doi: 10.1161/CIRCRESAHA.120.315913.
Ritchie Rebecca H, Abel E Dale,
Abstract
Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
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Metabolic and Molecular Imaging of the Diabetic Cardiomyopathy.
Circ Res2020 May;126(11):1628-1645. doi: 10.1161/CIRCRESAHA.120.315899.
Peterson Linda R, Gropler Robert J,
Abstract
The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to, well-established cardiovascular risk factors. A key contributor to this abnormal structural-functional relation is the complex interplay of myocardial metabolic remodeling, defined as the loss the flexibility in myocardial substrate metabolism and its downstream detrimental effects, such as mitochondrial dysfunction, inflammation, and fibrosis. In parallel with the growth in understanding of these biological underpinnings has been developmental advances in imaging tools such as positron emission tomography and magnetic resonance imaging and spectroscopy that permit the detection and in many cases quantification, of the processes that typifies the myocardial metabolic remodeling in diabetic cardiomyopathy. The imaging readouts can be obtained in both preclinical models of diabetes mellitus and patients with diabetes mellitus facilitating the bi-directional movement of information between bench and bedside. Moreover, imaging biomarkers provided by these tools are now being used to enhance discovery and development of therapies designed to reduce the myocardial effects of diabetes mellitus through metabolic modulation. In this review, the use of these imaging tools in the patient with diabetes mellitus from a mechanistic, therapeutic effect, and clinical management perspective will be discussed.
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Therapeutic approaches to diabetic cardiomyopathy: Targeting the antioxidant pathway.
Prostaglandins Other Lipid Mediat2020 May;():106454. doi: S1098-8823(20)30047-2.
Arad Michael, Waldman Maayan, Abraham Nader G, Hochhauser Edith,
Abstract
The global epidemic of cardiovascular disease continues unabated and remains the leading cause of death both in the US and worldwide. In the current review we summarize the available therapies for diabetes and cardiovascular disease in diabetics. Clearly, the current approaches to diabetic heart disease often target the manifestations and certain mediators but not the specific pathways leading to myocardial injury, remodeling and dysfunction. Better understanding of the molecular events determining the evolution of diabetic cardiomyopathy will provide insight into the development of specific and targeted therapies. This review reflects a dramatic increase in understanding the role of enhanced inflammatory response, ROS production, fibrosis in diabetic heart, as well as the contribution of Cyp-P450-epoxygenase-derived epoxyeicosatrienoic acid (EET), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1? (PGC-1??), Heme Oxygenase (HO)-1 and 20-HETE in pathophysiology and therapy of cardiovascular disease. PGC-1??increases production of the HO-1 which has a major role in protecting the heart against oxidative stress, microcirculation and mitochondrial dysfunction. This review focuses on potential drugs and their downstream targets, PGC-1??and HO-1, as major loci for developing therapeutic approaches beside diet and lifestyle modification for the treatment and prevention of heart disease associated with obesity and diabetes.
Copyright © 2020. Published by Elsevier Inc.
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Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs.
Cardiovasc Diabetol2020 May;19(1):62. doi: 10.1186/s12933-020-01041-4.
Packer Milton,
Abstract
Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)-effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.
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Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat.
Front Physiol2020 ;11():381. doi: 10.3389/fphys.2020.00381.
Xie Yebin, Huang Yu, Ling Xiaoyu, Qin Haiou, Wang Min, Luo Beibei,
Abstract
Chemerin and its receptor CMKLR1 (a G-protein-coupled receptor) are inducers of inflammation, and play an important role in diabetic cardiomyopathy (DCM). In this study, we investigated the role of the chemerin/CMKLR1 axis in mediating inflammation and cell death in DCM. Sprague-Dawley rats, treated with a high-fat diet and low-dose of streptozotocin, were used as a DCM model. CMKLR1 expression was knocked down by siRNA (CMKLR1-siRNA) to evaluate the role of CMKLR1 in DCM. Chemerin-treated H9c2 cells were used to investigate the factors acting downstream of the chemerin/CMKLR1 axis. LDH release and EthD-III staining were used to measure the ratio of cell death . CMKLR1-siRNA and siRNA against nucleotide-binding oligomerization domain-like receptors 3 (NLRP3-siRNA) were used to explore the mechanism underlying chemerin-induced inflammation and cell death. The results showed that the expression of chemerin, CMKLR1, NLRP3, pro-caspase-1, activated caspase-1, and mature IL-1? was increased in the DCM model rat. Myocardium of DCM model rats exhibited fibrosis, hypertrophy, a disorganized ultrastructure, and impaired function. Pyroptosis was observed and . Silencing of CMKLR1 attenuated the expression of NLRP3 and activated caspase-1 and IL-1?. CMKLR1-siRNA treatment attenuated cardiac inflammation, fibrosis, hypertrophy, and pyroptosis, and improved cardiac function . Silencing of either CMKLR1 or NLRP3 suppressed the levels of activated caspase-1, IL-1?, and pyroptosis; however, silencing of both CMKLR1 and NLRP3 further decreased the levels of mature IL-1? and pyroptosis. Overall, the results showed that the chemerin/CMKLR1 axis contributed to the development of DCM and that the NLRP3 inflammasome mediated the chemerin/CMLR1-induced inflammation and pyroptosis. These data indicate that silencing of the gene might exert a protective effect against DCM.
Copyright © 2020 Xie, Huang, Ling, Qin, Wang and Luo.
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Matrix Metalloproteases and Cathepsin D in Human Serum do not Cleave Prolactin to Generate Vasoinhibin.
Clin Lab2020 May;66(5):. doi: 10.7754/Clin.Lab.2019.191017.
Triebel Jakob, Schauer Nicole, Zamora Magdalena, Moreno-Vega Aura Ileana, Escalera Gonzalo Martinez de la, Clapp Carmen, Bertsch Thomas,
Abstract
BACKGROUND:
Vasoinhibin is generated in the pituitary gland and in multiple target tissues by proteolytic cleavage of prolactin by matrix metalloproteinases and cathepsin D. A dysregulation of vasoinhibin generation appears to contribute to diabetic retinopathy and diabetic macular edema, retinopathy of prematurity, peripartum cardiomyopathy, and preeclampsia. Here, we investigate whether vasoinhibin is generated by matrix metalloproteinases and cathepsin D in human serum.
METHODS:
The abundance of matrix metalloproteinases 1, 2, 3, 8, 9, 10, 13, tissue inhibitors of metalloproteinases 1, 2, 4, and the activity of cathepsin D in serum samples were determined. Samples from healthy male (n = 3) and female (n = 2) subjects, pregnant subjects (n = 2), and patients with type 2 diabetes mellitus (n = 2) were investigated. The samples were incubated with recombinant prolactin at 37°C, under different pH, time, and buffer conditions. Prolactin and cleaved prolactin products were investigated by SDS-PAGE and western blotting.
RESULTS:
Matrix metalloproteases-1, -2, -3, -8, -9, -10, -13, TIMP-1, -2, and -4, and the activity of cathepsin D were detected in all sera. Full-length prolactin incubated with human sera, containing endogenous matrix metalloproteinases and cathepsin D, remained intact at neutral pH during a time frame from 1 to 24 hours. Partial enzymatic cleavage of prolactin resulting in the generation of a vasoinhibin-like 17 kDa peptide was observed in samples incubated at pH 3.4. Heat inactivation of the serum and the addition of an MMP inhibitor suppressed the generation of the 17 kDa peptide, indicating that its generation was MMP-mediated.
CONCLUSIONS:
Vasoinhibin generation by enzymatic cleavage of prolactin by matrix metalloproteases or cathepsin D does not occur in human serum at physiological pH. A limited proteolysis of prolactin, resulting in the generation of a vasoinhibin-like peptide with an apparent molecular weight of 17 kDa occurs in serum at acidic pH. The generation of vasoinhibin may require the cellular and tissue microenvironments.
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Incremental value of diastolic stress test in identifying subclinical heart failure in patients with diabetes mellitus.
Eur Heart J Cardiovasc Imaging2020 May;():. doi: jeaa070.
Nishi Tomoko, Kobayashi Yukari, Christle Jeffrey W, Cauwenberghs Nicholas, Boralkar Kalyani, Moneghetti Kegan, Amsallem Myriam, Hedman Kristofer, Contrepois Kévin, Myers Jonathan, Mahaffey Kenneth W, Schnittger Ingela, Kuznetsova Tatiana, Palaniappan Latha, Haddad Francois,
Abstract
AIMS:
Resting echocardiography is a valuable method for detecting subclinical heart failure (HF) in patients with diabetes mellitus (DM). However, few studies have assessed the incremental value of diastolic stress for detecting subclinical HF in this population.
METHODS AND RESULTS:
Asymptomatic patients with Type 2 DM were prospectively enrolled. Subclinical HF was assessed using systolic dysfunction (left ventricular longitudinal strain <16% at rest and <19% after exercise in absolute value), abnormal cardiac morphology, or diastolic dysfunction (E/e' > 10). Metabolic equivalents (METs) were calculated using treadmill speed and grade, and functional capacity was assessed by percent-predicted METs (ppMETs). Among 161 patients studied (mean age of 59?±?11?years and 57% male sex), subclinical HF was observed in 68% at rest and in 79% with exercise. Among characteristics, diastolic stress had the highest yield in improving detection of HF with 57% of abnormal cases after exercise and 45% at rest. Patients with revealed diastolic dysfunction during stress had significantly lower exercise capacity than patients with normal diastolic stress (7.3?±?2.1 vs. 8.8?±?2.5, P?10 (beta = -0.17) were independently associated with peak METs (combined R2 = 0.46). A network correlation map revealed the connectivity of peak METs and diastolic properties as central features in patients with DM.
CONCLUSION:
Diastolic stress test improves the detection of subclinical HF in patients with diabetes mellitus.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
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Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF-1/CXCR4 signalling pathway.
Eur J Heart Fail2020 May;():. doi: 10.1002/ejhf.1840.
Dang Zexu, Avolio Elisa, Thomas Anita C, Faulkner Ashton, Beltrami Antonio P, Cervellin Celeste, Carrizzo Albino, Maciag Anna, Gu Yue, Ciaglia Elena, Finato Nicoletta, Damato Antonio, Spinetti Gaia, Alenzi Aishah, Paisey Stephen J, Vecchione Carmine, Puca Annibale A, Madeddu Paolo,
Abstract
AIMS:
Homozygosity for a four-missense single-nucleotide polymorphism haplotype of the human BPIFB4 gene is enriched in long-living individuals. Delivery of this longevity-associated variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell-derived factor-1 (SDF-1). Here, we investigated if delivery of the LAV-BPIFB4 gene may attenuate the progression of diabetic cardiomyopathy.
METHODS AND RESULTS:
Compared with age-matched lean controls, diabetic db/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV-BPIFB4 gene therapy using an adeno-associated viral vector serotype 9 (AAV9). In contrast, AAV9 wild-type-BPIFB4 exerted no benefit. Interestingly, LAV-BPIFB4-treated mice showed increased SDF-1 levels in peripheral blood and myocardium and up-regulation of the cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF-1 up-regulation was instrumental to LAV-BPIFB4-induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF-1 CXCR4 receptor.
CONCLUSIONS:
In mice with type-2 diabetes, LAV-BPIFB4 gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes-induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.
© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Dendrobium officinale Attenuates Myocardial Fibrosis via Inhibiting EMT Signaling Pathway in HFD/STZ-Induced Diabetic Mice.
Biol Pharm Bull2020 ;43(5):864-872. doi: 10.1248/bpb.b19-01073.
Zeng Jie, Li Dongning, Li Zhubo, Zhang Jie, Zhao Xiaoyan,
Abstract
Cardiac fibrosis is a major contributor for diabetic cardiomyopathy and Dendrobium officinale possessed therapeutic effects on hyperglycemia and diabetic cardiomyopathy. To further investigate the possible mechanisms of the Dendrobium officinale on diabetic myocardial fibrosis in mice. Water-soluble extracts of Dendrobium officinale (DOE) from dry stem was analyzed by HPLC and phenol-sulfuric acid method. Diabetic mice were induced by intraperitoneal injection of streptozotocin (STZ) (30?mg/kg) for 4 consecutive days after intragastric administration of a high-fat diet (HFD) for 2 weeks. The groups were as follows: control group, model group, DOE low, medium, high dose group (75, 150, 300?mg/kg) and Metformin positive group (125?mg/kg). The results showed that DOE dose-dependently lower serum insulin, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and grew the high-density lipoprotein cholesterol (HDL-C) after 12 weeks of daily administration with DOE. Hematoxylin-eosin staining and Sirius red staining showed obvious amelioration of cardiac injury and fibrosis. In addition, the result of immunoblot indicated that DOE increased the expression of peroxisome proliferator activated receptor-? (PPAR-?), phosphorylation of insulin receptor substrate 1 (p-IRS1) and E-cadherin and repressed the expression of transforming growth factor ?1 (TGF-?1), phosphorylation of c-Jun N-terminal kinase (p-JNK), Twist, Snail1 and Vimentin. The present findings suggested that DOE ameliorated HFD/STZ-induced diabetic cardiomyopathy (DCM). The possible mechanism mainly associated with DOE accelerating lipid transport, inhibiting insulin resistant and suppressing fibrosis induced by epithelial mesenchymal transition (EMT).
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[Expression of NLRP1 inflammasomes in myocardial tissue of diabetic rats].
Nan Fang Yi Ke Da Xue Xue Bao2020 Jan;40(1):87-92. doi: 10.12122/j.issn.1673-4254.2020.01.14.
Rong Li, Sun Shuo, Zhu Feiyu, Zhao Yi, Gao Qin, Zhang Heng, Tang Bi, Wang Hongju, Kang Pinfang,
Abstract
OBJECTIVE:
To observe the expression of NLRP1 inflammasomes in myocardial tissues in rats with a high-fat and highsugar diet and in diabetic rats analyze the role of NLRP1 inflammasomes in the pathogenesis of diabetic cardiomyopathy.
METHODS:
Male SD rats were divided into normal control group, high-sugar and high-fat diet (HC) group and diabetes group. Rat models of diabetes were established by intraperitoneal injection of streptozotocin (STZ; 30 mg/kg). Serum levels of cholesterol (TC), triglyceride (TG), and fasting insulin (FINS) were measured after 8 weeks of feeding, and the insulin resistance index (IRI) and insulin sensitivity index (ISI) were calculated; Echocardiographic evaluation of cardiac structure and function was performed, and Western blotting and real-time fluorescent quantitative PCR (RT-qRCP) were used to detect the protein and mRNA expressions of NLRP1, ASC, and caspase 1 in the myocardial tissue.
RESULTS:
Compared with the control rats, the rats in the HC group had significantly increased body weight (BW), serum levels of TG and TC, mRNA expressions of NLRP1 and caspase 1, and the protein expression of NLRP1 ( < 0.01) without significant changes in FINS, IRI, ISI, or cardiac ultrasound findings ( > 0.05) or in myocardial ASC and caspase 1 protein expressions or serum levels of IL-1? and IL-18 ( > 0.05). In the diabetic rats, TC, TG, and FBG levels increased and FINS, ISI decreased significantly ( < 0.01); the left ventricular end-diastolic diameter (LVID) and the left ventricular end-systolic diameter (LVSD) increased while the ejection fraction (LVEF), short axis shortening rate (FS), and E/A ratio all decreased. The expressions of NLRP1/ASC/caspase 1 pathway mRNA and NLRP1 and caspase 1 proteins also increased but myocardium ASC protein expression did not show significant changes in the diabetic rats ( > 0.05). IL-1? and IL-18 levels were also significantly higher in the diabetic rats than in the control group ( < 0.05). Compared with those in HC group, the diabetic rats showed significantly increased serum FBG and decreased FINS, ISI and BW ( < 0.01) with decreased LVSD, LVEF and E/A ratio and increased levels of NLRP1 and caspase 1 protein expressions and serum L-1? and IL-18 levels ( < 0.01).
CONCLUSIONS:
Diabetes can cause abnormal changes in cardiac structure and functions and induce inflammatory response in the myocardium, which may be related to the activation of NLRP1/ASC/ caspase 1 inflammasomes.
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PDCD4 deficiency ameliorates left ventricular remodeling and insulin resistance in a rat model of type 2 diabetic cardiomyopathy.
BMJ Open Diabetes Res Care2020 Apr;8(1):. doi: e001081.
Zhang Jie, Zhang Meng, Yang Zhi, Huang Shanying, Wu Xiao, Cao Lei, Wang Xiaohong, Li Qian, Li Na, Gao Fei,
Abstract
OBJECTIVE:
Diabetic cardiomyopathy (DCM) is characterized by cardiac remodeling, dysfunction, and insulin resistance; however, the underlying mechanism has not been fully elucidated. Programmed cell death 4 (PDCD4) is a novel inflammation and apoptosis gene, but its role in type 2 DCM remains elusive. We aimed to determine if PDCD4 intervention improves DCM by affecting left ventricular remodeling, function, and insulin resistance.
RESEARCH DESIGN AND METHODS:
We designed a PDCD4 rat, established a type 2 diabetes animal model, and constructed a PDCD4 overexpressed adenovirus and PDCD4 small interfer RNA (siRNA) vectors to alter PDCD4 expression in H9c2 cardiomyocytes. Thereafter, glucose levels, lipid metabolism, echocardiography, and extent of myocardial fibrosis, inflammation, and apoptosis were compared in vivo and in vitro.
RESULTS:
PDCD4 deficiency improved insulin resistance, cardiac remodeling, and dysfunction in type 2 DCM rats and improved myocardial hypertrophy, fibrosis, inflammation, and apoptosis. Proliferation and transformation of cardiac fibroblasts was reduced via PDCD4 downregulation in vitro under high-glucose stimulation. Furthermore, PDCD4 regulated the myocardial phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathway in vivo and in vitro. PDCD4 intervention affected cardiac remodeling, dysfunction, and insulin resistance by influencing fibrosis, inflammation, and apoptosis via the PI3K-AKT pathway in vivo.
CONCLUSIONS:
PDCD4 knockdown protected against left ventricular remodeling, dysfunction, and insulin resistance in type 2 DCM rats. The underlying mechanisms may involve reducing cardiomyocyte apoptosis, inflammation, fibrosis, and normalized PI3K-AKT phosphorylation. To the best of our knowledge, our study is the first to report the effects and underlying mechanisms of PDCD4 in type 2 DCM. These results provide a potential new treatment avenue for improving the prognosis of patients with type 2 DCM.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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