Central neuregulin-1/ErbB signaling modulates cardiac function via sympathetic activity in pressure overload-induced heart failure

2014 ◽  
Vol 32 (4) ◽  
pp. 817-825 ◽  
Author(s):  
Ryuichi Matsukawa ◽  
Yoshitaka Hirooka ◽  
Koji Ito ◽  
Nobuhiro Honda ◽  
Kenji Sunagawa
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Sympathetic Activity ◽  
Pressure Overload ◽  
Neuregulin 1 ◽  
Erbb Signaling

scholarly journals Recently Approved and Under Investigation Drugs for Treating Patients with Heart Failure

2020 ◽  
Vol 16 (3) ◽  
pp. 202-211
Author(s):  
Yaniel Castro-Torres ◽  
Richard E. Katholi
Keyword(s):  
Heart Failure ◽  
Clinical Practice ◽  
Mineralocorticoid Receptor ◽  
Sodium Current ◽  
Mineralocorticoid Receptor Antagonists ◽  
Neuregulin 1 ◽  
Reduced Ejection Fraction ◽  
Vasoactive Peptides ◽  
Patients With Heart Failure ◽  
Erbb Signaling

: Heart Failure (HF) represents a leading cause of morbidity and mortality worldwide. Despite the recent advances in the treatment of this condition, patients´ prognosis remains unfavorable in most cases. Sacubitril/valsartan and ivabradine have been recently approved to improve clinical outcomes in patients with HF with reduced ejection fraction. Drugs under investigation for treating patients with HF encompass many novel mechanisms including vasoactive peptides, blocking inflammatory- mediators, natriuretic peptides, selective non-steroidal mineralocorticoid-receptor antagonists, myocardial β3 adrenoreceptor agonists, inhibiting the cytochrome C/cardiolipin peroxidase complex, neuregulin-1/ErbB signaling and inhibiting late inward sodium current. The aim of this manuscript is to review the main drugs under investigation for the treatment of patients with HF and give perspectives for their implementation into clinical practice.

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

2018 ◽  
Vol 115 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Andrea Grund ◽  
Malgorzata Szaroszyk ◽  
Janina K Döppner ◽  
Mona Malek Mohammadi ◽  
Badder Kattih ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Binding Protein ◽  
Treatment Strategies ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

Abstract 352: Myocardial Neuregulin-1/ErbB Signaling Is Impaired in the Setting of Post--Myocardial Infarction Heart Failure Complicated by Type 1 Diabetes Mellitus

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Oghenerukevwe Odiete ◽  
Kathleen E Dennis ◽  
Douglas B Sawyer ◽  
Michael F Hill
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 1 Diabetes ◽  
Protein Expression ◽  
Type 1 Diabetes Mellitus ◽  
Neuregulin 1 ◽  
Erbb Signaling ◽  
Type 1 Dm

Background: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) are at heightened risk for the subsequent development of heart failure (HF). Despite the worse outcomes, investigations into the pathophysiological mechanisms that contribute to the increased frequency of HF after MI in the type 1 DM heart remain scarce. Neuregulin-1 (NRG-1), along with the ErbB family of receptor tyrosine kinases through which NRG-1 ligands signal, have been shown to be intimately involved in mediating cardiac recovery after MI. However, the impact of type 1 DM on this signaling system post-MI remains to be elucidated. Therefore, in the present study, we examined myocardial NRG-1/ErbB signaling during post-MI HF in the presence of type 1 DM. Methods: Type 1 DM was induced in male Sprague-Dawley rats via a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left anterior descending (LAD) coronary artery. Residual left ventricular (LV) function was assessed by echocardiography at 4 weeks post-MI. Following echocardiographic assessment, NRG-1, ErbB2, and ErbB4 protein expression was assessed in the remote, surviving LV myocardium of DM and non-DM rats using Western blot techniques. Results: LV Fractional Shortening (FS) and LV Ejection Fraction (EF) were significantly lower in the DM + MI group compared to the MI group ([LVFS: DM + MI, 17.9 ± 0.7 (n=6) vs. MI, 25.2 ± 2.2 (n=6), p <0.05; LVEF: DM + MI, 35.5 ± 1.4 (n=6) vs. MI, 47.5 ± 3.5 (n=6), p <0.05]), indicating an increased functional severity of HF in the diabetic post-MI group. The weight of myocardial scar caused by the infarction was not significantly different between the MI groups ([DM + MI, 0.19 ± 0.02 g (n=4) vs. MI, 0.20 ± 0.03 g (n=4), p =0.70]). ErbB2, ErbB4, and NRG-1 protein expression levels were all significantly lower in the DM + MI group compared to the MI group. Conclusions: These findings demonstrate that type 1 DM impairs myocardial NRG-1/ErbB signaling in response to MI, which may contribute to the accelerated progression of subsequent HF. Augmentation of NRG-1 or its downstream signaling pathways may represent a novel therapeutic strategy for ameliorating post-MI HF in the setting of type 1 DM.

scholarly journals Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

2018 ◽  
Vol 115 (20) ◽  
pp. E4661-E4669 ◽  
Author(s):  
Xudong Liao ◽  
Yuyan Shen ◽  
Rongli Zhang ◽  
Keiki Sugi ◽  
Neelakantan T. Vasudevan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Late Phase ◽  
Myeloid Cells ◽  
Pressure Overload ◽  
Genetic Mutations ◽  
Nonischemic Cardiomyopathy ◽  
Resident Macrophage ◽  
Temporal And Spatial

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

scholarly journals Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

2017 ◽  
Vol 113 (6) ◽  
pp. 633-643 ◽  
Author(s):  
Jihe Li ◽  
Keyvan Yousefi ◽  
Wen Ding ◽  
Jayanti Singh ◽  
Lina A. Shehadeh
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Rna Aptamer ◽  
Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

scholarly journals Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction

2021 ◽  
Author(s):  
Igor N Zelko ◽  
Sujith Dassanayaka ◽  
Marina V Malovichko ◽  
Caitlin M Howard ◽  
Lauren F Garrett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Cardiac Function ◽  
Cardiac Tissue ◽  
Pressure Overload ◽  
Endothelial Activation ◽  
Air Exposure ◽  
Benzene Exposure ◽  
Increased Risk

Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5-2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.

scholarly journals Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure

2020 ◽  
Vol 5 (5) ◽  
pp. 484-497 ◽  
Author(s):  
Jhansi Dyavanapalli ◽  
Jeannette Rodriguez ◽  
Carla Rocha dos Santos ◽  
Joan B. Escobar ◽  
Mary Kate Dwyer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Pressure Overload

Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Bianca C Bernardo ◽  
Sally S Nguyen ◽  
Catherine E Winbanks ◽  
Xiao-Ming Gao ◽  
Esther J Boey ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Pressure Overload ◽  
Post Treatment ◽  
Locked Nucleic Acid ◽  
Luciferase Assay ◽  
Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

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