Abstract 421: Norepinephrine Catabolism Drives Cardiac Fibroblast Activation via Monoamine Oxidase Activity and Rage/β-adrenergic Signaling

The mitochondrial enzyme monoamine oxidase A (MAO-A) plays an increasingly appreciated role in cardiac remodeling induced by diabetes and ischemic injury. Oxidative deamination of norepinephrine (NE) by MAO-A generates 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and H 2 O 2 . Isolation and quantification of catechol-modified proteins from cardiac fibroblast lysate using an aminophenylboronic acid resin showed an MAO-dependent accumulation of catechol adducts in NE-treated cells (P<0.05). Our lab has previously observed increased expression and activity of MAO in myocardium of diabetes patients compared with age-matched nondiabetic patients. Moreover, preliminary data suggest that catecholaldehydes and other biogenic aldehydes might contribute to the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy via pro-fibrotic signaling mechanisms. We hypothesize that NE activates fibroblasts by both canonical pathways (i.e, adrenergic receptors) and by monoamine oxidase-mediated catabolism and activation of the receptor for advanced glycation endproducts (RAGE). Treatment of cardiac fibroblasts with NE (1 μM) resulted in accelerated proliferation, enhanced collagen I & III secretion, robust increases in mitochondrial and total cellular ROS, and upregulated pro-fibrotic gene expression. These effects were abrogated by co-administration of RAGE antagonist FPS-ZM1, MAO inhibitors, β-blocker propranolol, and the aldehyde scavenger carnosine (P<0.05). These findings suggest that NE (and other catecholamines) may influence extracellular matrix remodeling via multiple pathways, including adrenergic and also RAGE, via MAO-mediated catabolism.

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Soluble St2 Induces Cardiac Fibroblast Activation and Collagen Synthesis via Neuropilin-1

Cells ◽

10.3390/cells9071667 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1667 ◽

Cited By ~ 1

Author(s):

Lara Matilla ◽

Vanessa Arrieta ◽

Eva Jover ◽

Amaia Garcia-Peña ◽

Ernesto Martinez-Martinez ◽

...

Keyword(s):

Collagen Synthesis ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Interleukin 1 ◽

Cardiac Fibroblast ◽

Pathogenic Role ◽

Fibroblast Activation ◽

Neuropilin 1 ◽

Human Cardiac Fibroblasts

Circulating levels of soluble interleukin 1 receptor-like 1 (sST2) are increased in heart failure and associated with poor outcome, likely because of the activation of inflammation and fibrosis. We investigated the pathogenic role of sST2 as an inductor of cardiac fibroblasts activation and collagen synthesis. The effects of sST2 on human cardiac fibroblasts was assessed using proteomics and immunodetection approaches to evidence the upregulation of neuropilin-1 (NRP-1), a regulator of the profibrotic transforming growth factor (TGF)-β1. In parallel, sST2 increased fibroblast activation, collagen and fibrosis mediators. Pharmacological inhibition of nuclear factor-kappa B (NF-κB) restored NRP-1 levels and blocked profibrotic effects induced by sST2. In NRP-1 knockdown cells, sST2 failed to induce fibroblast activation and collagen synthesis. Exogenous NRP-1 enhanced cardiac fibroblast activation and collagen synthesis via NF-κB. In a pressure overload rat model, sST2 was elevated in association with cardiac fibrosis and was positively correlated with NRP-1 expression. Our study shows that sST2 induces human cardiac fibroblasts activation, as well as the synthesis of collagen and profibrotic molecules. These effects are mediated by NRP-1. The blockade of NF-κB restored NRP-1 expression, improving the profibrotic status induced by sST2. These results show a new pathogenic role for sST2 and its mediator, NRP-1, as cardiac fibroblast activators contributing to cardiac fibrosis.

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The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

International Journal of Molecular Sciences ◽

10.3390/ijms21030970 ◽

2020 ◽

Vol 21 (3) ◽

pp. 970 ◽

Cited By ~ 2

Author(s):

Scott P. Levick ◽

Alexander Widiapradja

Keyword(s):

High Glucose ◽

Effector Cell ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Cardiac Fibroblast ◽

Review Article ◽

Cardiomyocyte Hypertrophy ◽

Preserved Ejection Fraction ◽

Microvascular Damage ◽

And Function

Diabetic cardiomyopathy involves remodeling of the heart in response to diabetes that includes microvascular damage, cardiomyocyte hypertrophy, and cardiac fibrosis. Cardiac fibrosis is a major contributor to diastolic dysfunction that can ultimately result in heart failure with preserved ejection fraction. Cardiac fibroblasts are the final effector cell in the process of cardiac fibrosis. This review article aims to describe the cardiac fibroblast phenotype in response to high-glucose conditions that mimic the diabetic state, as well as to explain the pathways underlying this phenotype. As such, this review focuses on studies conducted on isolated cardiac fibroblasts. We also describe molecules that appear to oppose the pro-fibrotic actions of high glucose on cardiac fibroblasts. This represents a major gap in knowledge in the field that needs to be addressed.

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Cardiac Fibroblast Diversity

Annual Review of Physiology ◽

10.1146/annurev-physiol-021119-034527 ◽

2020 ◽

Vol 82 (1) ◽

pp. 63-78 ◽

Cited By ~ 8

Author(s):

Michelle D. Tallquist

Keyword(s):

Extracellular Matrix ◽

Single Cell ◽

Future Development ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Pathological Condition ◽

Cardiac Fibroblast ◽

Lineage Tracing ◽

Single Cell Sequencing ◽

Disease States

Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of these cells as determined by lineage tracing and single-cell sequencing in development, adult, and disease states. These recent advances in our understanding of the fibroblast provide a platform for future development of novel therapeutics to combat cardiac fibrosis.

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Are Coumarin Derivatives The New Keys in Depression Treatment? In silico Key-lock Fitting Analysis of Coumarin Derivatives with Monoamine Oxidase-A

JOURNAL OF PHARMACEUTICAL CHEMISTRY ◽

10.14805/jphchem.2020.art119 ◽

2020 ◽

Vol 7 ◽

Author(s):

Dilara Karaman ◽

Kemal YELEKCI ◽

Serkan ALTUNTAS

Keyword(s):

Monoamine Oxidase ◽

Protein Interactions ◽

In Silico ◽

Monoamine Oxidase A ◽

Coumarin Derivatives ◽

Discovery Studio ◽

Mao B ◽

Drug Candidates ◽

Mao A ◽

Molecular Modeling Studies

The research of ligand-protein interactions with in silico molecular modeling studies on the atomic level gives an opportunity to be understood the pharmacokinetic metabolism of anti-depressant drug candidates. Monoamine oxidase (MAO) enzymes are important targets for the treatment of depressive disorder. MAOs have two isoforms as MAO-A and MAO-B being responsible for catalyzing of neurological amines. In this study a new series of coumarin derivatives were designed for selective and reversible inhibition of MAO-A enzyme. 3rd, 5th and 7th positions were selected to be placed of five different side groups. Docking procedures of each ligand in M series of these novel 125 compounds were executed with 10 runs by using AutoDock4.2 software. Docking results were analyzed via Discovery Studio 3.1 (Biovia Inc.). The most promising compounds were M118 and M123 according to selectivity index, SI (MAO-B/MAO-A)=180 fold and 209 fold and Ki values 7.25 nM and 12.01 nM, respectively. Overall, the current study provided significant knowledge for the development of new anti-depressant drugs.

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Polymorphisms of the serotonin transporter and Monoamine Oxidase A gene in patients with metastatic midgut carcinoid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4557 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4557-4557

Author(s):

A. van der Horst-Schrivers ◽

E. de Vries ◽

P. Willemse ◽

I. Kema ◽

T. Links ◽

...

Keyword(s):

Monoamine Oxidase ◽

Serotonin Transporter ◽

Promoter Region ◽

Carcinoid Tumors ◽

Monoamine Oxidase A ◽

Independent Effect ◽

Clinical Effects ◽

Cox Regression Analysis ◽

Midgut Carcinoid ◽

Mao A

4557 Background: In patients with metastatic midgut carcinoid tumors increased serotonin secretion is related to the carcinoid syndrome and mortality. Free serotonin is taken up via the serotonin transporter (5-HTT) in the liver and the lung and metabolized to 5- hydroxyindolacetic acid (5-HIAA) by Monoamine Oxidase A (MAO-A). The 5-HTT gene has a functional polymorphism in the promoter region (5-HTTPLR), with a short (S, less active) and long (L) allele and a polymorphic region in the second intron with variable number tandem repeats (VNTR-2). The MAO-A gene contains a length polymorphism in its promoter region (MAOA-LPR). To determine the clinical effects of the serotonin metabolizing capacity of individual patients, the association between different genotypes and symptoms (flushes and diarrhea) and survival was studied. Methods: 107 patients with metastatic midgut carcinoid tumors were genotyped for 5-HTTPLR, VNTR-2 and MAO-A-LPR. Differences were tested using Chi-square test and survival according to genotypes was analyzed using Kaplan Meier survival curves and tested with a log rank test. The independent effect of genotypes on survival was studied with multivariate Cox regression analysis with adjustments for the urinary 5-HIAA level, age at presentation and the presence of liver metastases. Results: The various genotypic variants were not related to flushes or diarrhea. Patients with the SS variant of 5-HTTLPR had a shorter median survival (45 months, 95% Confidence Interval (CI) 0.50–90) compared to patients with the LS (113 months, 95% CI 53–172) and the LL variant (90 months, 95% CI 64–115) (P=0.02). After adjustment, survival in patients with the SS variant remained worse with an odds ratio of 0.43 (95% CI 0.23–0.83; P=0.009) and 0.63 (95% CI 0.33–1.11; P=0.1) compared to patients with the LS and the LL variant respectively. Survival was not influenced by the VNTR-2 or MAOA-LPR. Conclusions: The SS genotype of the 5-HTTLPR is independently associated with a worse survival in patients with metastatic midgut carcinoid tumors. No significant financial relationships to disclose.

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Involvement of Monoamine Oxidase a (MAO-A) in mitochondrial fission and autophagy during aging

European Heart Journal ◽

10.1093/eurheartj/eht308.p1856 ◽

2013 ◽

Vol 34 (suppl 1) ◽

pp. P1856-P1856 ◽

Cited By ~ 1

Author(s):

F. Vigneron ◽

C. Guilbeau-Frugier ◽

A. Parini ◽

J. Mialet-Perez

Keyword(s):

Monoamine Oxidase ◽

Mitochondrial Fission ◽

Monoamine Oxidase A ◽

Mao A

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Brain monoamine oxidase A in hyperammonemia is regulated by NMDA receptors

Open Life Sciences ◽

10.2478/s11535-009-0016-2 ◽

2009 ◽

Vol 4 (3) ◽

pp. 321-326

Author(s):

Elena Kosenko ◽

Yury Kaminsky

Keyword(s):

Oxidative Stress ◽

Nmda Receptor ◽

Monoamine Oxidase ◽

Nmda Receptors ◽

Monoamine Oxidase A ◽

Mk 801 ◽

Mao A ◽

Vitro Effect

AbstractMitochondrial enzyme monoamine oxidase A (MAO-A) generates hydrogen peroxide (H2O2) and is up-regulated by Ca2+ and presumably by ammonia. We hypothesized that MAO-A may be under the control of NMDA receptors in hyperammonemia. In this work, the in vivo effects of single dosing with ammonia and NMDA receptor antagonist MK-801 and the in vitro effect of Ca2+ on MAO-A activity in isolated rat brain mitochondria were studied employing enzymatic procedure. Intraperitoneal injection of rats with ammonia led to an increase in MAO-A activity in mitochondria indicating excessive H2O2 generation. Calcium added to isolated mitochondria stimulated MAO-A activity by as much as 84%. MK-801 prevented the in vivo effect of ammonia, implying that MAO-A activation in hyperammonemia is mediated by NMDA receptors. These data support the conclusion that brain mitochondrial MAO-A is regulated by the function of NMDA receptors. The enzyme can contribute to the oxidative stress associated with hyperammonemic conditions such as encephalopathy and Alzheimer’s disease. The attenuation of the oxidative stress highlights MAO-A inactivation and NMDA receptor antagonists as sources of novel avenues in the treatment of mental disorders.

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Monoamine oxidase A (MAO A) inhibitors decrease glioma progression

Oncotarget ◽

10.18632/oncotarget.7283 ◽

2016 ◽

Vol 7 (12) ◽

pp. 13842-13853 ◽

Cited By ~ 24

Author(s):

Swati Kushal ◽

Weijun Wang ◽

Vijaya Pooja Vaikari ◽

Rajesh Kota ◽

Kevin Chen ◽

...

Keyword(s):

Monoamine Oxidase ◽

Monoamine Oxidase A ◽

Mao A ◽

Glioma Progression

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Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.771466 ◽

2021 ◽

Vol 9 ◽

Author(s):

Tinghui Shao ◽

Yujia Xue ◽

Mingming Fang

Keyword(s):

Chloride Channel ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Cardiac Fibroblast ◽

Transcriptional Level ◽

Potent Inducer ◽

Potential Implication ◽

Over Expression ◽

E Box ◽

Epigenetic Repression

Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-β, a potent inducer of FMyT. TGF-β repressed Clca2 expression at the transcriptional level likely via the E-box element between −516 and −224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-β induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.

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