scholarly journals BET Protein-Mediated Transcriptional Regulation in Heart Failure

2021 ◽  
Vol 22 (11) ◽  
pp. 6059
Author(s):  
Talha Ijaz ◽  
Michael A. Burke
Keyword(s):  
Heart Failure ◽  
Gene Transcription ◽  
Transforming Growth Factor Beta ◽  
Gene Networks ◽  
Complex Disease ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Systolic Dysfunction ◽  
Disease Process

Heart failure is a complex disease process with underlying aberrations in neurohormonal systems that promote dysregulated cellular signaling and gene transcription. Over the past 10 years, the advent of small-molecule inhibitors that target transcriptional machinery has demonstrated the importance of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in regulating gene transcription in multiple mouse models of cardiomyopathy. BETs bind to acetylated histone tails and transcription factors to integrate disparate stress signaling networks into a defined gene expression program. Under myocardial stress, BRD4, a BET family member, is recruited to superenhancers and promoter regions of inflammatory and profibrotic genes to promote transcription elongation. Whole-transcriptome analysis of BET-dependent gene networks suggests a major role of nuclear-factor kappa b and transforming growth factor-beta in the development of cardiac fibrosis and systolic dysfunction. Recent investigations also suggest a prominent role of BRD4 in maintaining cardiomyocyte mitochondrial respiration under basal conditions. In this review, we summarize the data from preclinical heart failure studies that explore the role of BET-regulated transcriptional mechanisms and delve into landmark studies that define BET bromodomain-independent processes involved in cardiac homeostasis.

Abstract 3444: Arachidonic 12-lipoxygenase Promotes the Development of Cardiac Fibrosis and Heart Failure via Induction of Monocyte Chemoattractant Protein-1

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yosuke Kayama
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
12 Lipoxygenase

To elucidate the molecular mechanisms of heart failure, we examined expression of 8800 genes in the heart of hypertensive heart failure model (Dahl salt-sensitive rats). DNA chip analysis revealed that 12-lipoxygenase (12-LOX) was markedly upregulated in the failing heart. 12-LOX is a key enzyme of the arachidonic cascade that metabolizes eicosanoid. Until recently, 12-LOX has been reported to play an important role in the development of atherogenesis, diabetes, and neurogenerative disease. However, the role of 12-LOX in heart failure has not been examined. To determine whether increased expression of 12-LOX causes heart failure, we established transgenic mice that overexpress 12-LOX only in cardiomyocytes. Echocardiogra-phy showed that 12-LOX transgenic mice developed systolic dysfunction from as early as 16 weeks old. Histological analysis revealed that cardiac fibrosis was increased in 12-LOX transgenic mice with advancing age, which was associated with infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (MCP-1) was upregulated in 12-LOX transgenic mice compared to those of wild-type mice. In vitro experiments demonstrated that treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12-LOX, increased MCP-1 expression in cardiac fibroblast and endothelial cells but not in cardiomyocytes. To determine the role of MCP-1 in the heart of 12LOX transgenic mice, we treated these mice with 7ND, an inhibitor of MCP-1, for 32 weeks. Chronic treatment with 7ND attenuated infiltration of macrophages into the myocardium and prevented systolic dysfunction and cardiac fibrosis in 12-LOX transgenic mice. Likewise, disruption of 12-LOX significantly reduced expression of MCP-1 and infiltration of macrophages in the heart, thereby inhibiting cardiac remodeling after myocardial infarction. Our in vitro and in vivo results suggest that cardiac 12-LOX is critically involved in the development of heart failure and that inhibition of 12-LOX will be a novel target for the treatment of this condition.

Abstract 1: Opposing Roles for Endoglin and Soluble Endoglin in Cardiac Remodeling and Heart Failure

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Navin K Kapur ◽  
Szuhuei Wilson ◽  
Adil A Yunis ◽  
Corey Baker ◽  
Mark J Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transforming Growth Factor Beta ◽  
Neutralizing Antibodies ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Dependent Manner ◽  
Soluble Endoglin

Transforming growth factor beta-1 (TGFb1) promotes cardiac fibrosis. The transmembrane co-receptor Endoglin (Eng; CD105) facilitates TGFb1 signaling via SMAD effector proteins. In contrast, a circulating form of soluble endoglin (sEng) inhibits TGFb1 signaling in vascular endothelium. We recently reported that increased sEng levels in human serum correlate with clinical indices of heart failure severity. Therefore, we tested the hypothesis that Eng and sEng mediate opposing effects on cardiac fibrosis in heart failure. In male, wild-type mice (WT), Eng expression increased in the left ventricle (LV) after 2, 4, and 10 weeks of thoracic aortic constriction (TAC) accompanied by progressive LV fibrosis and hypertrophy. In contrast to WT mice, Eng haploinsufficient (Eng +/− ) mice had preserved LV function (FS%: 78±4 vs 22±16, Eng +/− vs WT, p<0.01) and improved survival [88%(7/8) vs 50%(4/8), Eng +/− vs WT, p<0.001) after 10 weeks of TAC. Reduced LV fibrosis was observed in Eng +/− mice, while LV mass, cardiomyocyte hypertrophy, and calcineurin, SerCA, and bMHC expression were comparable to WT after TAC. Capillary density was significantly higher in Eng +/− mice after TAC compared to WT. LV SMAD phosphorylation (pSMAD) after TAC was studied and a preferential increase was observed in pSMAD1/5/8 expression in Eng +/− mice as compared to WT mice, in which cardiac pSmad2/3 expression was increased. The dependence of TGFb1 induced collagen synthesis on Eng expression was tested in vitro using human cardiac fibroblasts (hCF). Neutralizing antibodies and siRNA against Eng each attenuated TGFb1 induced collagen synthesis. In contrast, conditioned media from cells transfected with an adenovirus over-expressing sEng attenuated pSMAD2/3 expression and TGFb1 induced collagen synthesis in hCF. Treatment of hCF with recombinant sEng blocked TGFb1 induced collagen synthesis in a dose-dependent manner, confirming an inhibitory role of sEng. These results indicate that Eng and sEng mediate opposite effects on TGFb1 induced collagen synthesis. Reduced Eng expression uncouples cardiac fibrosis from cardiomyocyte hypertrophy, promotes SMAD1/5/8-signaling, and enhances angiogenesis. Eng may represent a novel therapeutic target to improve survival in heart failure.

scholarly journals EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling

2017 ◽  
Vol 121 (6) ◽  
pp. 617-627 ◽  
Author(s):  
Sheng-an Su ◽  
Du Yang ◽  
Yue Wu ◽  
Yao Xie ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Intramyocardial Injection

Rationale: Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified. Objective: We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process. Methods and Results: EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-β (transforming growth factor-β)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil–coil domain and DNA-binding domain of Stat3 mediated the interaction. Conclusions: This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.

scholarly journals Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β–Smad3 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yinhui Wang ◽  
Kun Yu ◽  
Chengcheng Zhao ◽  
Ling Zhou ◽  
Jia Cheng ◽  
...  
Keyword(s):  
Myosin Heavy Chain ◽  
Diabetic Cardiomyopathy ◽  
Heavy Chain ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Endogenous Protein ◽  
Matrix Metallopeptidase

Follistatin (FST) is an endogenous protein that irreversibly inhibits TGF-β superfamily members and plays an anti-fibrotic role in other diseases. However, the role of FST in diabetic cardiomyopathy remains unclear. In this study, we investigated the effects of FST on diabetic cardiomyopathy. The expression of FST was downregulated in the hearts of db/db mice. Remarkably, overexpressing FST efficiently protected against cardiac dysfunction. In addition, overexpression of FST promoted cardiac hypertrophy with an unchanged expression of atrial natriuretic peptide (ANP) and the ratio of myosin heavy chain-β/myosin heavy chain-α (MYH7/MYH6). Furthermore, FST reduced cardiac fibrosis and the production of reactive oxygen species (ROS), and enhanced matrix metallopeptidase 9 (MMP9) activities in db/db mouse hearts. We also observed that overexpressing FST decreased the level of transforming growth factor beta (TGF-β) superfamily members and the phosphorylation of Smad3; consistently, in vitro experiments also verified the above results. Our findings revealed the cardioprotective role of FST in attenuating diabetic cardiomyopathy through its anti-fibrotic effects through the TGF-β–Smad3 pathway and provided a promising therapeutic strategy for diabetic cardiomyopathy.

Galectin-3 in Heart Failure – Linking Fibrosis, Remodelling and Progression

2010 ◽  
Vol 6 (2) ◽  
pp. 33 ◽  
Author(s):  
Christopher R deFilippi ◽  
G Michael Felker ◽  
◽  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Risk Stratification ◽  
Cardiac Fibrosis ◽  
The Elderly ◽  
Preserved Ejection Fraction ◽  
Heart Failure Patients ◽  
Large Populations ◽  
Galectin 3

For many with heart failure, including the elderly and those with a preserved ejection fraction, both risk stratification and treatment are challenging. For these large populations and others there is increasing recognition of the role of cardiac fibrosis in the pathophysiology of heart failure. Galectin-3 is a novel biomarker of fibrosis and cardiac remodelling that represents an intriguing link between inflammation and fibrosis. In this article we review the biology of galectin-3, recent clinical research and its application in the management of heart failure patients.

scholarly journals Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Jayarami Reddy Medapati ◽  
Deepthi Rapaka ◽  
Veera Raghavulu Bitra ◽  
Santhosh Kumar Ranajit ◽  
Girija Sankar Guntuku ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Morphological Changes ◽  
Serum Levels ◽  
Cb1 Receptors ◽  
Protective Effects ◽  
Renal Hypertrophy ◽  
Necrosis Factor Alpha

Abstract Background The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks. Results The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001). Conclusions From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy. Graphical abstract

scholarly journals Beyond Natriuretic Peptides for Diagnosis and Management of Heart Failure

2017 ◽  
Vol 63 (1) ◽  
pp. 211-222 ◽  
Author(s):  
Nasrien E Ibrahim ◽  
James L Januzzi
Keyword(s):  
Heart Failure ◽  
Renal Dysfunction ◽  
Complex Disease ◽  
Disease Process ◽  
Clinical Information ◽  
Matrix Remodeling ◽  
Injury Death ◽  
Societal Burden ◽  
Myocardial Stretch ◽  
Novel Biomarkers

Abstract BACKGROUND Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost and morbidity and mortality. Natriuretic peptide (NP) testing is now widely used to support diagnosis, prognostication, and management of patients with HF, but NPs come with limitations, including vulnerability to the presence of obesity, atrial fibrillation, and renal dysfunction, for example. Beyond the NPs, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF, and possibly to personalize care for those affected through better individual phenotyping. CONTENT In this review we discuss novel biomarkers by dividing them into categories based on major pathophysiologic pathways they represent including myocardial stretch/stress, cardiac extracellular matrix remodeling, cardiomyocyte injury/death, oxidative stress, inflammation, neurohumoral activation, and renal dysfunction. SUMMARY Given the limitations of NPs, along with the complex physiology in HF, it is logical to consider utilization of novel biomarkers providing orthogonal biological and clinical information. Several novel HF biomarkers have shown promise but have substantial expectations to meet before being used clinically. Nonetheless, it is reasonable to expect the future lies in the application of multibiomarker panels for the improvement in management of HF and the personalization of care.

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