Abstract 372: MicroRNA-9 Inhibits Hyperglycemia-induced Cardiac Pyroptosis by Targeting ELAVL1

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Prince Jeyabal ◽  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana Suresh Babu ◽  
Shashirekha Krishnamurthy ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Glucose ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Therapeutic Implications ◽  
Caspase 1 ◽  
Ventricular Cardiomyocytes ◽  
Nlrp3 Expression

Diabetic cardiomyopathy is a common complication in patients with diabetes and is associated with underlying chronic inflammation and cardiac cell death, subsequently leading to left ventricular dysfunction and heart failure. ELAV-like protein 1 (ELAVL1, mRNA stabilizing protein) and NLRP3 activation (inflammasome complex protein)-mediated IL-1beta synthesis play a critical role in the progression of heart failure. However, ELAVL1 regulation of pyroptosis (caspase-1-mediated programmed apoptosis) and associated IL-1beta release in cardiomyocytes, especially under diabetic condition, remains elusive. Human diabetic, non-diabetic heart tissues, human ventricular cardiomyocytes and rat cardiomyoblasts exposed to high glucose (HG) were used for our studies. Our data demonstrates that human ventricular cardiomyocytes exposed to high glucose condition showed significant increase in ELAVL1 and NLRP3 expression with a concomitant increase in caspase-1 and IL-1 beta expression. Furthermore, human cardiac tissue from diabetic patients showed increased ELAVL1, caspase-1 and NLRP3 expression as compared to non-diabetic hearts. Intriguingly, ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1beta suppression. Interestingly, miRNA-9 expression significantly reduces in high glucose treated cardiomyocytes and in human diabetic hearts. Bioinformatics analysis and target validation assays showed that miR-9 directly targets ELAVL1. Inhibition of miR-9 up regulates ELAVL1 expression and activates caspase-1. Alternatively, miR-9 mimics attenuate hyperglycemia-induced ELAVL1 and inhibit cardiomyocyte pyroptosis. To our knowledge, this is the first report to demonstrate the role of miR-9/ELAVL1 in hyperglycemia-induced cardiac pyroptosis. Taken together our study highlights the potential therapeutic implications in preventing cardiomyocyte cell loss in human diabetic failing heart.

Abstract MP216: Identification Of Novel Phosphoprotein Signaling Pathways In Human Dilated Cardiomyopathy By Integrative Proteomic And Phosphoproteomic Analysis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Cristine J Reitz ◽  
Marjan Tavassoli ◽  
Da Hye Kim ◽  
Sina Hadipour-Lakmehsari ◽  
Saumya Shah ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Tissue ◽  
Regulatory Element ◽  
Critical Role ◽  
Left Ventricular ◽  
Confocal Imaging ◽  
Intercalated Disc ◽  
Bioinformatics Analyses ◽  
Tissue Samples ◽  
And Function

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, yet the majority of the underlying signaling mechanisms remain poorly characterized. Protein phosphorylation is a key regulatory element with profound effects on the activity and function of signaling networks; however, there is a lack of comprehensive phosphoproteomic studies in human DCM patients. We assessed the hypothesis that an integrative phosphoproteomics analysis of human DCM would reveal novel phosphoprotein candidates involved in disease pathophysiology. Combined proteomic and phosphoproteomic analysis of explanted left ventricular tissue samples from DCM patients ( n =4) and non-failing controls ( n =4) identified 5,570 unique proteins with 13,624 corresponding phosphorylation sites. From these analyses, we identified αT-catenin as a unique candidate protein with a cluster of 4 significantly hyperphosphorylated sites in DCM hearts ( P <0.0001), with no change in total αT-catenin expression at the protein level. Bioinformatics analyses of human datasets and confocal imaging of human and mouse cardiac tissue show highly cardiac-enriched expression of αT-catenin, localized to the cardiomyocyte intercalated disc. High resolution 3-dimensional reconstruction shows elongated intercalated disc morphology in DCM hearts (10.07±0.76 μm in controls vs. 17.20±1.87 μm in DCM, P <0.05, n =3/group), with significantly increased colocalization of αT-catenin with the intercalated disc membrane protein N-cadherin (Pearson’s coefficient 0.55±0.04 in controls vs. 0.71±0.02 in DCM, P <0.05, n =3/group). To investigate the functional role of cardiac αT-catenin phosphorylation, we overexpressed WT protein vs. non-phosphorylatable forms based on the loci identified in DCM hearts, in adult mouse cardiomyocytes using lentiviral transduction. Confocal imaging revealed significant internalization of the phospho-null form, as compared to the prominent intercalated disc staining of the WT protein (17.78±0.79% of WT vs. 9.25±0.49% of 4A mutant, P <0.0001, n =50 cells/group). Together, these findings suggest a critical role for αT-catenin phosphorylation in maintaining cardiac intercalated disc organization in human DCM.

scholarly journals Hyperuricemia and the Risk of Heart Failure: Pathophysiology and Therapeutic Implications

2021 ◽  
Vol 12 ◽  
Author(s):  
Ke Si ◽  
Chijing Wei ◽  
Lili Xu ◽  
Yue Zhou ◽  
Wenshan Lv ◽  
...  
Keyword(s):  
Heart Failure ◽  
Vascular Inflammation ◽  
Cardiovascular Effects ◽  
Daily Practice ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Current Evidence ◽  
Free Oxygen Radical ◽  
Positive Role ◽  
Therapeutic Implications

The association between hyperuricemia and cardiovascular disease (CVD) has been reported and studied in the past two decades. Xanthine oxidase (XO) induced uric acid (UA) serves as a risk factor and has the independent prognostic and functional impact of heart failure (HF), but whether it plays a positive role in the pathogenesis of HF has remained unclear. Growing evidence suggest the up-regulated XO avtivity and increased production of free oxygen radical (ROS) correspondingly are the core pathogenesis of HF with hyperuricemia, which results in a whole cluster of pathophysiologic cardiovascular effects such as oxidative stress, endothelial dysfunction, vascular inflammation, left ventricular (LV) dysfunction as well as insulin resistance (IR). The use of XO inhibition represents a promising therapeutic choice in patients with HF due to its dual effect of lowering serum UA levels as well as reducing ROS production. This review will discuss the pathophysiologic mechanisms of hyperuricemia with HF, the targeted therapeutic interventions of UA lowering therapies (ULT) with XO inhibition and mechanism underlying beneficial effects of ULT. In addition, the review also summarizes current evidence on the role of ULT in HF and compares CV risk between allopurinol and febuxostat for practical and clinical purposes. Guidelines and implementation of CV risk management in daily practice will be discussed as well.

scholarly journals Effect of Acute Hyperglycemia on Left Ventricular Contractile Function in Diabetic Patients with and without Heart Failure: Two Randomized Cross-Over Studies

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53247 ◽  
Author(s):  
Roni Nielsen ◽  
Helene Nørrelund ◽  
Ulla Kampmann ◽  
Hans Erik Bøtker ◽  
Niels Møller ◽  
...  
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Acute Hyperglycemia

ErbB2 Expression on Left Ventricular Epicardial Endothelial Cells and CD105+ Cells is Decreased in Patients with Diabetes Mellitus.

2021 ◽  
Author(s):  
Joanne T. deKay ◽  
Joshua Carver ◽  
Bailey Shevenell ◽  
Angela M. Kosta ◽  
Sergey Tsibulnikov ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Cell Surface ◽  
High Glucose ◽  
Artery Bypass ◽  
Surface Expression ◽  
Left Ventricular ◽  
Cell Surface Expression ◽  
Erbb Receptors ◽  
Diabetic Patients

Abstract Background We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105+ cells obtained from cardiac biopsies of patients undergoing coronary artery bypass grafting surgery (CABG). Methods Endothelial cells and CD105+ non-endothelial cells were freshly isolated from LV epicardial biopsies obtained from 15 subjects with diabetes mellitus (DM) and 8 controls. The expression of ErbB recepotrs was examined using multiparametric flow cytometry. Human microvascular endothelial cells (HMEC-1) and LV epicardial CD105+ non-endothelial cells were used to determine the effect of high glucose on ADAM10-dependent cleavage of ErbB receptors. Results We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2 on both endothelial cells and CD105+ non-endothelial cells. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high glucose in HMEC-1 and LV epicardial CD105+ non-endothelial cells, using a novel flow cytometric approach to simultaneously determine the total level, cell surface expression, and phosphorylation of ErbB2. Incubation of cells in the presence of 25 mM D-glucose resulted in decreased cell surface expression of ErbB2. We also found high expression of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) on both endothelial cells and CD105+ non-endothelial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. Conclusions We suggest that high glucose depresses ErbB receptor signaling in endothelial cells and cardiac progenitor cells via the promotion of ADAM10-dependent cleavage of ErbB2 at the cell surface, thus contributing to vascular dysfunction and adverse remodeling seen in diabetic patients.

Abstract P477: A Novel SMYD1 Variant (c.302A>G) Leads To Dilated Cardiomyopathy And Biventricular Heart Failure.

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Marta Szulik ◽  
Miguel Reyes-Mugica ◽  
Daniel F Marker ◽  
Lina Ghaloul-Gonzalez ◽  
Sarah Franklin
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Cardiac Tissue ◽  
De Novo ◽  
Cardiac Development ◽  
Left Ventricular ◽  
Histopathological Analysis ◽  
Loss Of Function ◽  
Adult Mice ◽  
Heterozygous Variant

The lysine methyltransferase SMYD1 was first identified in mice and shown to be important for embryonic cardiac development. Subsequently, we reported the first analysis of SMYD1 in adult myocardium and demonstrated that cardiomyocyte-specific loss of SMYD1 lead to progressive cardiac hypertrophy and heart failure, and showed that this enzyme is necessary to maintain metabolic homeostasis through transcriptional regulation of mitochondrial energetics in adult mice. While SMYD1 has been the subject of several additional studies in zebrafish and mice, since it was first identified, only in the last few years have human patients been identified with variants in the SMYD1 gene thought to be responsible for their cardiomyopathies. Specifically, two patients have been identified to date, the first patient displaying hypertrophic cardiomyopathy had a de novo heterozygous variant (c.814T>C) and the second patient with left ventricular non-compaction cardiomyopathy and arrhythmias had a truncating heterozygous variant (c.675delA). Here we report a third patient with biventricular heart failure containing a homozygous variant (c.302A>G; p.Asn101S) in the SMYD1 gene which was identified by a whole exome sequencing. Our histopathological analysis of cardiac tissue and skeletal muscle from the proband showed abnormalities in myofibrillar organization in both cardiac and skeletal muscle suggesting that SMYD1 is necessary for sarcomere assembly and organization. In addition, we observe markedly abnormal myocardium with extensive fibrosis and multifocal calcification, and our ultrastructural (EM) analysis revealed presence of abnormal mitochondria with reduced and irregular or lost cristae. Lastly, we have performed structural modeling of SMYD1 containing the p.Asn101Ser variant (N101S) and report how this variant may affect the enzymatic activity of SMYD1 due to its proximity to the substrate binding site. The identification of this novel variant constitutes the third patient with a SMYD1 variant displaying cardiomyopathy and provides insights into the molecular functionality of this protein. In addition, this is the first analysis of tissue from a patient expressing a SMYD1 variant which provides critical insights into the role of SMYD1 in the heart and how loss of function mutations can effect cardiac physiology.

3269Impact of type 2 diabetes on incidence and phenotype of heart failure in patients with atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Polovina ◽  
I Milinkovic ◽  
G Krljanac ◽  
I Veljic ◽  
I Petrovic-Djordjevic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Type 2 Diabetes ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Diabetic Patients ◽  
History Of ◽  
New Onset

Abstract Background Type 2 diabetes (T2DM) portends adverse prognosis in patients with atrial fibrillation (AF). Whether T2DM independently increases the risk of incident heart failure (HF) in AF is uncertain. Also, HF phenotype developing in patients with vs. those without T2DM has not been characterised. Purpose In AF patients without a history of prior HF, we aimed to assess: 1) the impact of T2DM on the risk of new-onset HF; and 2) the association between T2DM and HF phenotype developing during the prospective follow-up. Methods We included diabetic and non-diabetic AF patients, without a history of HF. Baseline T2DM status was inferred from medical history, haemoglobin A1c levels and oral glucose tolerance test. Study outcome was the first hospital admission or emergency department treatment for new-onset HF during the prospective follow-up. The phenotype of new-onset HF was determined by echocardiographic exam performed following clinical stabilisation (at hospital discharge, or within a month after HF diagnosis). HF phenotype was defined as HFrEF (left ventricular ejection fraction [LVEF] <40%), HFmrEF (LVEF 40–49%) or HFpEF (LVEF≥50%). Cox regression analyses adjusted for age, sex, baseline LVEF, comorbidities, smoking status, alcohol intake, AF type (paroxysmal vs. non-paroxysmal) and T2DM treatment was used to analyse the association between T2DM and incident HF. Results Among 1,288 AF patients without prior HF (mean age: 62.1±12.7 years; 61% male), T2DM was present in 16.5%. Diabetic patients had higher mean baseline LVEF compared with nondiabetic patients (50.0±6.2% vs. 57.6±9.0%; P<0.001). During the median 5.5-year follow-up, new-onset HF occurred in 12.4% of patients (incidence rate, 2.9; 95% confidence interval [CI], 2.5–3.3 per 100 patient-years). Compared with non-diabetic patients, those with T2DM had a hazard ratio of 2.1 (95% CI, 1.6–2.8; P<0.001) for new-onset HF, independent of baseline LVEF or other factors. In addition, diabetic patients had a significantly greater decline in covariate-adjusted mean LVEF (−10.4%; 95% CI, −9.8% to −10.8%) at follow-up, compared with nondiabetic patients (−4.0%; 95% CI, −3.8% to −4.2%), P<0.001. The distribution of HF phenotypes at follow-up is presented in Figure. Among patients with T2DM, HFrEF (56.9%) was the most common phenotype of HF, whereas in patients without T2DM, HF mostly took the phenotype of HFpEF (75.0%). Conclusions T2DM is associated with an independent risk of new-onset HF in patients with AF and confers a greater decline in LVEF compared to individuals without T2DM. HFrEF was the most prevalent presenting phenotype of HF in AF patients with T2DM.

scholarly journals NLRP3 Inflammasome Expression and Signaling in Human Diabetic Wounds and in High Glucose Induced Macrophages

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Xiaotian Zhang ◽  
Jiezhi Dai ◽  
Li Li ◽  
Hua Chen ◽  
Yimin Chai
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Chronic Wound ◽  
Diabetic Patients ◽  
Glucose Stimulation ◽  
M1 Macrophage ◽  
Novel Target ◽  
Diabetic Wounds ◽  
Nlrp3 Expression ◽  
Wound Tissue

Introduction. To investigate the contribution and mechanism of NLRP3 inflammasome expression in human wounds in diabetes mellitus and in high glucose induced macrophages. Methods. In the present study, we compared the expression of NLRP3 inflammasome in debridement wound tissue from diabetic and nondiabetic patients. We also examined whether high glucose induces NLRP3 inflammasome expression in cultures THP-1-derived macrophages and the influence on IL-1β expression. Results. The expressions of NLRP3, caspase1, and IL-1β, at both the mRNA and protein level, were significantly higher in wounds of diabetic patients compared with nondiabetic wounds (P<0.05). High glucose induced a significant increase in NLRP3 inflammasome and IL-1β expression in THP-1-derived macrophages. M1 macrophage surface marker with CCR7 was significantly upregulated after high glucose stimulation. SiRNA-mediated silencing of NLRP3 expression downregulates the expression of IL-1β. Conclusion. The higher expression of NLRP3, caspase1, and secretion of IL-1β, signaling, and activation might contribute to the hyperinflammation in the human diabetic wound and in high glucose induced macrophages. It may be a novel target to treat the DM patients with chronic wound.

The Transcription Factor Gfi1 Negatively Regulates NLRP3 inflammasome-Mediated IL-1β Secretion in Macrophages

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4119-4119
Author(s):  
Zhu Liuluan ◽  
Meng Qingcai ◽  
Liang Shuntao ◽  
Li Guoli ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Biologically Active ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
Inflammasome Activation ◽  
Nlrp3 Gene ◽  
Caspase 1 ◽  
Reporter Assays ◽  
Nlrp3 Expression

Abstract Background: IL-1β secretion is tightly controlled at the transcriptional and post-translational levels. The NLRP3 inflammasome, a multiprotein complex composed of NOD-like receptor-containing pyrin 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and pro-caspase-1, plays a critical role in IL-1β maturation at the latter stage. NLRP3 expression is a limiting factor for inflammasome activation, and therefore, negative regulation of this factor is necessary to control excessive IL-1β production during sepsis. Previously, we showed that the transcriptional repressor Gfi1 inhibits pro-IL-1β transcription and the IL-1β level is significantly higher in serum of LPS-treated Gfi1-/- than wild-type (WT) mice. The present study revealed that Gfi1 regulates IL-1β secretion through inhibiting NLRP3 inflammasome activation in macrophages. Methods and Results: Bone marrow-derived macrophages (BMDM) from WT and Gfi1-/- mice were primed with LPS and stimulated with ATP. Compared with WT cells, those lacking Gfi1 induced a significant increase in IL-1β in the culture medium (Figure 1A). Western blot disclosed moderate elevation of pro-IL-1β, along with a more dramatic increase in mature IL-1β and cleaved caspase-1 in Gfi1-deficient BMDMs, suggesting that Gfi1 inhibits IL-1β maturation. Consistently, real-time PCR findings showed increased NLRP3 mRNA in Gfi1-deficient macrophages (Figure 1B), implying that Gfi1 affects expression of NLRP3 at the transcriptional level. To determine the mechanism underlying the regulatory activity of Gfi1 on NLRP3 expression, the mouse NLRP3 promoter was screened, leading to the identification of a putative binding site for Gfi1 (GRE1, located at nt -1210/-1207). In dual luciferase reporter assays performed with WT and GRE1 mutant promoters, the inhibitory effect of Gfi1 on NLRP3 transcription was significantly reversed upon GRE1 mutation. EMSA and ChIP assays performed to further establish the function of GRE1 (Figure 2A) validated the in vivo and in vitro interactions between Gfi1 and the GRE1 element, and consequently, a direct transcriptional repression effect on the NLRP3 gene. NF-κB p65 activates NLRP3 transcription through binding two elements in its promoter region, and Gfi1 interferes with activity through direct interactions with p65. Accordingly, we mutated the binding elements of p65 (NRE1 and NRE2) in the NLRP3 promoter. Dual luciferase reporter assays showed that mutation of NRE1 almost entirely suppressed activation of p65 while mutation of NRE2 exerted no effect, indicating that NF-κB p65 specifically interacts with NRE1 for the activation in this system. EMSA studies further confirmed that Gfi1 strongly competes for binding of NF-κB p65 with NRE1, antagonizing interactions between p65 and the NLRP3 promoter (Figure 2B). Maximum suppression of NLRP3 promoter activity by Gfi1 was observed with the NLRP3 promoter reporter containing a NRE1/ GRE1 double mutant (Figure 2C). Conclusions: In summary, we propose a “dual repression model” mechanism of Gfi1 in the regulation of NLRP3 expression. Once activated by LPS, NF-κB promotes NLRP3 expression by binding to the cis-element, NRE1, in turn, promoting assembly of the NLRP3 inflammasome to generate biologically active IL-1β. Meanwhile, Gfi1 is induced to control LPS-induced inflammation. Gfi1 directly inhibits NLRP3 transcription by binding the GRE1 site or blocks NF-κB-mediated NLRP3 transcription via interactions with NF-κB p65. Both modes of action lead to suppression of IL-1β release from macrophages in response to LPS stimulation. The present data, along with previous reports showing that Gfi1 restricts pro-IL-1β transcription, indicate that Gfi1 plays pivotal roles in regulating IL-1β production at both transcriptional and post-translational levels. These findings provide novel evidence that should aid in the development of future anti-inflammatory therapies to prevent IL-1β-induced tissue injury and mortality during sepsis. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Revascularization for Stable Chronic Total Occlusion is Essential for Diabetic Patient with Heart Failure

2019 ◽  
Author(s):  
Yunfeng Yan ◽  
Mingduo Zhang ◽  
Zhuo Ma ◽  
Zilong Zhang ◽  
Fei Yuan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Subgroup Analysis ◽  
Chronic Total Occlusion ◽  
Treatment Strategies ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Diabetic Patients ◽  
Cardiac Events ◽  
Total Occlusion ◽  
Ventricular Ejection Fraction

Abstract Background Revascularization is the recommended treatment strategy for patients with heart failure (HF) and coronary artery disease (CAD). However, chronic total occlusion (CTO) is less attempt. Furthermore, there were conflicting debates on if diabetic HF patients gained benefits from revascularization. As to CTO revascularization, no study answered if it offered benefits to diabetic HF patients. Methods Diabetic patients with stable CTO and HF were consecutively enrolled in this retrospective cohort study. Based on treatment strategies to the CTO vessel, patients were assigned to successful revascularization (CTO-SR) or medical therapy (CTO-MT) group. The primary endpoints were major adverse cardiac events (MACE). Subgroup analysis were performed based on left ventricular ejection fraction (LVEF) and relevant baseline variables. Results A population of 680 patients were enrolled in the present study: 344 patients in the CTO-MT group, and 336 patients in the CTO-SR group. After a median follow-up of 34 months, CTO-SR was superior to CTO-MT in MACE (adjusted hazard ratio [HR]: 0.462, 95% conference interval [CI]: 0.337-0.634), which could mainly due to the superiority in cardiac-death and TVR. Propensity matching analysis also confirmed CTO-SR’s superiority (HR: 0.494 [0.337-0.725]). Subgroup analysis further confirmed a consistent superiority in patients with LVEF≥40%, but not in those with LVEF<40%.Conclusions For patients with diabetes, HF and stable CTO, CTO-SR was superior to CTO-MT. CTO-SR’s superiority was consistent in patients with LVEF≥40%, but not for patients with LVEF<40%. Trial registration This study was not registered in an open access database.

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