Publications by authors named "Nikolaos G Frangogiannis"

158 Publications

Platelet-derived growth factor (PDGF) therapy in myocardial infarction: Challenges and opportunities.

Int J Cardiol 2021 Oct 18;341:74-75. Epub 2021 Aug 18.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2021.08.022DOI Listing
October 2021

Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities.

Adv Drug Deliv Rev 2021 09 29;176:113904. Epub 2021 Jul 29.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA. Electronic address:

In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.
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http://dx.doi.org/10.1016/j.addr.2021.113904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444077PMC
September 2021

Reperfused vs. nonreperfused myocardial infarction: when to use which model.

Am J Physiol Heart Circ Physiol 2021 07 11;321(1):H208-H213. Epub 2021 Jun 11.

Department of Pharmacology, Faculty of Medicine, Dalhousie University, Saint John, New Brunswick, Canada.

There is a lack of understanding in the cardiac remodeling field regarding the use of nonreperfused myocardial infarction (MI) and reperfused MI in animal models of MI. This Perspectives summarizes the consensus of the authors regarding how to select the optimum model for your experiments and is a part of ongoing efforts to establish rigor and reproducibility in cardiac physiology research.
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http://dx.doi.org/10.1152/ajpheart.00234.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321810PMC
July 2021

Collagen denaturation in the infarcted myocardium involves temporally distinct effects of MT1-MMP-dependent proteolysis and mechanical tension.

Matrix Biol 2021 05 25;99:18-42. Epub 2021 May 25.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, United States. Electronic address:

Tissue injury results in profound alterations in the collagen network, associated with unfolding of the collagen triple helix, proteolytic degradation and generation of fragments. In the infarcted myocardium, changes in the collagen network are critically involved in the pathogenesis of left ventricular rupture, adverse remodeling and chronic dysfunction. We hypothesized that myocardial infarction is associated with temporally and spatially restricted patterns of collagen denaturation that may reflect distinct molecular mechanisms of collagen unfolding. We used a mouse model of non-reperfused myocardial infarction, and in vitro assays in fibroblast-populated collagen lattices. In healing infarcts, labeling with collagen hybridizing peptide (CHP) revealed two distinct patterns of collagen denaturation. During the inflammatory and proliferative phases of infarct healing, collagen denaturation was pericellular, localized in close proximity to macrophages and myofibroblasts. qPCR array analysis of genes associated with matrix remodeling showed that Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) is markedly upregulated in infarct macrophages and fibroblasts, suggesting its involvement in pericellular collagen denaturation. In vitro, MT1-MMP-mediated pericellular collagen denaturation is involved in cardiac fibroblast migration. The effects of MT1-MMP on collagen denaturation and fibroblast migration involve the catalytic site, and require hemopexin domain-mediated actions. In contrast, during the maturation phase of infarct healing, extensive collagen denaturation was noted in the hypocellular infarct, in the infarct border zone and in the mitral valve annulus, in the absence of MT1-MMP. In vitro, mechanical tension in attached collagen lattices was sufficient to induce peripheral collagen denaturation. Our study suggests that in healing infarcts, early pericellular collagen denaturation may be important for migration of macrophages and reparative myofibroblasts in the infarct. Extensive denaturation of collagen fibers is noted in mature scars, likely reflecting mechanical tension. Chronic collagen denaturation may increase susceptibility of the matrix to proteolysis, thus contributing to progressive cardiac dilation and post-infarction heart failure.
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http://dx.doi.org/10.1016/j.matbio.2021.05.005DOI Listing
May 2021

Diabetic fibrosis.

Biochim Biophys Acta Mol Basis Dis 2021 04 28;1867(4):166044. Epub 2020 Dec 28.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

Diabetes-associated morbidity and mortality is predominantly due to complications of the disease that may cause debilitating conditions, such as heart and renal failure, hepatic insufficiency, retinopathy or peripheral neuropathy. Fibrosis, the excessive and inappropriate deposition of extracellular matrix in various tissues, is commonly found in patients with advanced type 1 or type 2 diabetes, and may contribute to organ dysfunction. Hyperglycemia, lipotoxic injury and insulin resistance activate a fibrotic response, not only through direct stimulation of matrix synthesis by fibroblasts, but also by promoting a fibrogenic phenotype in immune and vascular cells, and possibly also by triggering epithelial and endothelial cell conversion to a fibroblast-like phenotype. High glucose stimulates several fibrogenic pathways, triggering reactive oxygen species generation, stimulating neurohumoral responses, activating growth factor cascades (such as TGF-β/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs) and stimulating the AGE-RAGE axis, and upregulating fibrogenic matricellular proteins. Although diabetes-activated fibrogenic signaling has common characteristics in various tissues, some organs, such as the heart, kidney and liver develop more pronounced and clinically significant fibrosis. This review manuscript summarizes current knowledge on the cellular and molecular pathways involved in diabetic fibrosis, discussing the fundamental links between metabolic perturbations and fibrogenic activation, the basis for organ-specific differences, and the promises and challenges of anti-fibrotic therapies for diabetic patients.
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http://dx.doi.org/10.1016/j.bbadis.2020.166044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867637PMC
April 2021

Chemokines in cardiac fibrosis.

Curr Opin Physiol 2021 Feb 19;19:80-91. Epub 2020 Oct 19.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY.

Several members of the chemokine family are involved in regulation of fibrosis. This review manuscript discusses the role of the chemokines in the pathogenesis of myocardial fibrosis. The CC chemokine CCL2 exerts fibrogenic actions through recruitment and activation of monocytes and macrophages expressing its receptor, CCR2. Other CC chemokines may also contribute to fibrotic remodeling by recruiting subsets of fibrogenic macrophages. CXC chemokines containing the ELR motif may exert pro-fibrotic actions, through recruitment of activated neutrophils and subsequent formation of neutrophil extracellular traps (NETs), or via activation of fibrogenic monocytes. CXCL12 has also been suggested to exert fibrogenic actions through effects on fibroblasts and immune cells. In contrast, the CXCR3 ligand CXCL10 was found to reduce cardiac fibrosis, inhibiting fibroblast migration. Chemokines are critical links between inflammation and fibrosis in myocardial disease and may be promising therapeutic targets for patients with heart failure accompanied by prominent inflammation and fibrosis.
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http://dx.doi.org/10.1016/j.cophys.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665080PMC
February 2021

The role of Smad signaling cascades in cardiac fibrosis.

Cell Signal 2021 01 5;77:109826. Epub 2020 Nov 5.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

Most myocardial pathologic conditions are associated with cardiac fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix (ECM) proteins. Although replacement fibrosis plays a reparative role after myocardial infarction, excessive, unrestrained or dysregulated myocardial ECM deposition is associated with ventricular dysfunction, dysrhythmias and adverse prognosis in patients with heart failure. The members of the Transforming Growth Factor (TGF)-β superfamily are critical regulators of cardiac repair, remodeling and fibrosis. TGF-βs are released and activated in injured tissues, bind to their receptors and transduce signals in part through activation of cascades involving a family of intracellular effectors the receptor-activated Smads (R-Smads). This review manuscript summarizes our knowledge on the role of Smad signaling cascades in cardiac fibrosis. Smad3, the best-characterized member of the family plays a critical role in activation of a myofibroblast phenotype, stimulation of ECM synthesis, integrin expression and secretion of proteases and anti-proteases. In vivo, fibroblast Smad3 signaling is critically involved in scar organization and exerts matrix-preserving actions. Although Smad2 also regulates fibroblast function in vitro, its in vivo role in rodent models of cardiac fibrosis seems more limited. Very limited information is available on the potential involvement of the Smad1/5/8 cascade in cardiac fibrosis. Dissection of the cellular actions of Smads in cardiac fibrosis, and identification of patient subsets with overactive or dysregulated myocardial Smad-dependent fibrogenic responses are critical for design of successful therapeutic strategies in patients with fibrosis-associated heart failure.
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http://dx.doi.org/10.1016/j.cellsig.2020.109826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727442PMC
January 2021

Cardiac fibrosis.

Cardiovasc Res 2021 05;117(6):1450-1488

Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA.

Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4], and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.
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http://dx.doi.org/10.1093/cvr/cvaa324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152700PMC
May 2021

Fact and Fiction About Fibroblast to Endothelium Conversion: Semantics and Substance of Cellular Identity.

Circulation 2020 10 26;142(17):1663-1666. Epub 2020 Oct 26.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594161PMC
October 2020

The significance of COVID-19-associated myocardial injury: how overinterpretation of scientific findings can fuel media sensationalism and spread misinformation.

Eur Heart J 2020 10;41(39):3836-3838

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer G46B, Bronx, NY 10461, USA.

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http://dx.doi.org/10.1093/eurheartj/ehaa727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599034PMC
October 2020

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure.

Cardiovasc Drugs Ther 2020 12 9;34(6):849-863. Epub 2020 Sep 9.

Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY, 10461, USA.

Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrix-degrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.
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http://dx.doi.org/10.1007/s10557-020-07071-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479403PMC
December 2020

Validation of diagnostic criteria and histopathological characterization of cardiac rupture in the mouse model of nonreperfused myocardial infarction.

Am J Physiol Heart Circ Physiol 2020 11 4;319(5):H948-H964. Epub 2020 Sep 4.

Division of Cardiology, Department of Medicine, The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York.

In patients with myocardial infarction (MI), cardiac rupture is an uncommon but catastrophic complication. In the mouse model of nonreperfused MI, reported rupture rates are highly variable and depend not only on the genetic background and sex of animals but also on the method used for documentation of rupture. In most studies, diagnosis of cardiac rupture is based on visual inspection during autopsy; however, criteria are poorly defined. We performed systematic histopathological analysis of whole hearts from C57BL/6J mice dying after nonreperfused MI and evaluated the reliability of autopsy-based criteria in identification of rupture. Moreover, we compared the cell biological environment of the infarct between rupture-related and rupture-independent deaths. Histopathological analysis documented rupture in 50% of mice dying during the first week post-MI. Identification of a gross rupture site was highly specific but had low sensitivity; in contrast, hemothorax had high sensitivity but low specificity. Mice with rupture had lower myofibroblast infiltration, accentuated macrophage influx, and a trend toward reduced collagen content in the infarct. Male mice had increased mortality and higher incidence of rupture. However, infarct myeloid cells harvested from male and female mice at the peak of the incidence of rupture had comparable inflammatory gene expression. In conclusion, the reliability of autopsy in documentation of rupture in infarcted mice is dependent on the specific criteria used. Macrophage-driven inflammation and reduced activation of collagen-secreting reparative myofibroblasts may be involved in the pathogenesis of post-MI cardiac rupture. We show that cardiac rupture accounts for 50% of deaths in C57BL/6J mice undergoing nonreperfused myocardial infarction protocols. Overestimation of rupture events in published studies likely reflects the low specificity of hemothorax as a criterion for documentation of rupture. In contrast, identification of a gross rupture site has high specificity and low sensitivity. We also show that mice dying of rupture have increased macrophage influx and attenuated myofibroblast infiltration in the infarct. These findings are consistent with a role for perturbations in the balance between inflammatory and reparative responses in the pathogenesis of postinfarction cardiac rupture. We also report that the male predilection for rupture in infarcted mice is not associated with increased inflammatory activation of myeloid cells.
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http://dx.doi.org/10.1152/ajpheart.00318.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701358PMC
November 2020

Extracellular matrix-derived peptides in tissue remodeling and fibrosis.

Matrix Biol 2020 09 8;91-92:176-187. Epub 2020 May 8.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, New York.

Alterations in the composition of the extracellular matrix (ECM) critically regulate the cellular responses in tissue repair, remodeling, and fibrosis. After injury, proteolytic degradation of ECM generates bioactive ECM fragments, named matricryptins, exposing cryptic sites with actions distinct from the parent molecule. Matricryptins contribute to the regulation of inflammatory, reparative, and fibrogenic cascades through effects on several different cell types both in acute and chronic settings. Fibroblasts play a major role in matricryptin generation not only as the main cellular source of ECM proteins, but also as producers of matrix-degrading proteases. Moreover, several matricryptins exert fibrogenic or reparative actions by modulating fibroblast phenotype and function. This review manuscript focuses on the mechanisms of matricyptin generation in injured and remodeling tissues with an emphasis on fibroblast-matricryptin interactions.
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http://dx.doi.org/10.1016/j.matbio.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434701PMC
September 2020

Chemokines in Myocardial Infarction.

J Cardiovasc Transl Res 2021 02 15;14(1):35-52. Epub 2020 May 15.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY, USA.

In the infarcted myocardium, cardiomyocyte necrosis triggers an intense inflammatory reaction that not only is critical for cardiac repair, but also contributes to adverse remodeling and to the pathogenesis of heart failure. Both CC and CXC chemokines are markedly induced in the infarcted heart, bind to endothelial glycosaminoglycans, and regulate leukocyte trafficking and function. ELR+ CXC chemokines (such as CXCL8) control neutrophil infiltration, whereas CC chemokines (such as CCL2) mediate recruitment of mononuclear cells. Moreover, some members of the chemokine family (such as CXCL10 and CXCL12) may mediate leukocyte-independent actions, directly modulating fibroblast and vascular cell function. This review manuscript discusses our understanding of the role of the chemokines in regulation of injury, repair, and remodeling following myocardial infarction. Although several chemokines may be promising therapeutic targets in patients with myocardial infarction, clinical implementation of chemokine-based therapeutics is hampered by the broad effects of the chemokines in both injury and repair.
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http://dx.doi.org/10.1007/s12265-020-10006-7DOI Listing
February 2021

Extracellular Matrix in Ischemic Heart Disease, Part 4/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2219-2235

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Victor Chang Cardiac Research Institute and St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address:

Myocardial ischemia and infarction, both in the acute and chronic phases, are associated with cardiomyocyte loss and dramatic changes in the cardiac extracellular matrix (ECM). It has long been appreciated that these changes in the cardiac ECM result in altered mechanical properties of ischemic or infarcted myocardial segments. However, a growing body of evidence now clearly demonstrates that these alterations of the ECM not only affect the structural properties of the ischemic and post-infarct heart, but they also play a crucial and sometimes direct role in mediating a range of biological pathways, including the orchestration of inflammatory and reparative processes, as well as the pathogenesis of adverse remodeling. This final part of a 4-part JACC Focus Seminar reviews the evidence on the role of the ECM in relation to the ischemic and infarcted heart, as well as its contribution to cardiac dysfunction and adverse clinical outcomes.
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http://dx.doi.org/10.1016/j.jacc.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269147PMC
May 2020

The role of Smad2 and Smad3 in regulating homeostatic functions of fibroblasts in vitro and in adult mice.

Biochim Biophys Acta Mol Cell Res 2020 07 14;1867(7):118703. Epub 2020 Mar 14.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America. Electronic address:

The heart contains an abundant fibroblast population that may play a role in homeostasis, by maintaining the extracellular matrix (ECM) network, by regulating electrical impulse conduction, and by supporting survival and function of cardiomyocytes and vascular cells. Despite an explosion in our understanding of the role of fibroblasts in cardiac injury, the homeostatic functions of resident fibroblasts in adult hearts remain understudied. TGF-β-mediated signaling through the receptor-activated Smads, Smad2 and Smad3 critically regulates fibroblast function. We hypothesized that baseline expression of Smad2/3 in fibroblasts may play an important role in cardiac homeostasis. Smad2 and Smad3 were constitutively expressed in normal mouse hearts and in cardiac fibroblasts. In cultured cardiac fibroblasts, Smad2 and Smad3 played distinct roles in regulation of baseline ECM gene synthesis. Smad3 knockdown attenuated collagen I, collagen IV and fibronectin mRNA synthesis and reduced expression of the matricellular protein thrombospondin-1. Smad2 knockdown on the other hand attenuated expression of collagen V mRNA and reduced synthesis of fibronectin, periostin and versican. In vivo, inducible fibroblast-specific Smad2 knockout mice and fibroblast-specific Smad3 knockout mice had normal heart rate, preserved cardiac geometry, ventricular systolic and diastolic function, and normal myocardial structure. Fibroblast-specific Smad3, but not Smad2 loss modestly but significantly reduced collagen content. Our findings suggest that fibroblast-specific Smad3, but not Smad2, may play a role in regulation of baseline collagen synthesis in adult hearts. However, at least short term, these changes do not have any impact on homeostatic cardiac function.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261645PMC
July 2020

Monocyte subsets as predictors of adverse events in patients with atherosclerosis.

Hellenic J Cardiol 2019 Sep - Oct;60(5):322-323. Epub 2019 Dec 14.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hjc.2019.11.009DOI Listing
June 2020

Editorial commentary: Myocardial fibrosis in genetic cardiomyopathies: A cause of dysfunction, or simply an epiphenomenon?

Trends Cardiovasc Med 2020 08 5;30(6):362-363. Epub 2019 Oct 5.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx NY, United States. Electronic address:

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http://dx.doi.org/10.1016/j.tcm.2019.09.009DOI Listing
August 2020

The Role of the TGF-β Superfamily in Myocardial Infarction.

Front Cardiovasc Med 2019 18;6:140. Epub 2019 Sep 18.

Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, United States.

The members of the transforming growth factor β (TGF-β) superfamily are essential regulators of cell differentiation, phenotype and function, and have been implicated in the pathogenesis of many diseases. Myocardial infarction is associated with induction of several members of the superfamily, including TGF-β1, TGF-β2, TGF-β3, bone morphogenetic protein (BMP)-2, BMP-4, BMP-10, growth differentiation factor (GDF)-8, GDF-11 and activin A. This manuscript reviews our current knowledge on the patterns and mechanisms of regulation and activation of TGF-β superfamily members in the infarcted heart, and discusses their cellular actions and downstream signaling mechanisms. In the infarcted heart, TGF-β isoforms modulate cardiomyocyte survival and hypertrophic responses, critically regulate immune cell function, activate fibroblasts, and stimulate a matrix-preserving program. BMP subfamily members have been suggested to exert both pro- and anti-inflammatory actions and may regulate fibrosis. Members of the GDF subfamily may also modulate survival and hypertrophy of cardiomyocytes and regulate inflammation. Important actions of TGF-β superfamily members may be mediated through activation of Smad-dependent or non-Smad pathways. The critical role of TGF-β signaling cascades in cardiac repair, remodeling, fibrosis, and regeneration may suggest attractive therapeutic targets for myocardial infarction patients. However, the pleiotropic, cell-specific, and context-dependent actions of TGF-β superfamily members pose major challenges in therapeutic translation.
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http://dx.doi.org/10.3389/fcvm.2019.00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760019PMC
September 2019

S100A8/A9 as a therapeutic target in myocardial infarction: cellular mechanisms, molecular interactions, and translational challenges.

Eur Heart J 2019 08;40(32):2724-2726

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA.

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http://dx.doi.org/10.1093/eurheartj/ehz524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703152PMC
August 2019

Fibroblasts in the Infarcted, Remodeling, and Failing Heart.

JACC Basic Transl Sci 2019 Jun 24;4(3):449-467. Epub 2019 Jun 24.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, New York.

Expansion and activation of fibroblasts following cardiac injury is important for repair but may also contribute to fibrosis, remodeling, and dysfunction. The authors discuss the dynamic alterations of fibroblasts in failing and remodeling myocardium. Emerging concepts suggest that fibroblasts are not unidimensional cells that act exclusively by secreting extracellular matrix proteins, thus promoting fibrosis and diastolic dysfunction. In addition to their involvement in extracellular matrix expansion, activated fibroblasts may also exert protective actions, preserving the cardiac extracellular matrix, transducing survival signals to cardiomyocytes, and regulating inflammation and angiogenesis. The functional diversity of cardiac fibroblasts may reflect their phenotypic heterogeneity.
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http://dx.doi.org/10.1016/j.jacbts.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610002PMC
June 2019

The cell biological basis for primary unloading in acute myocardial infarction.

Int J Cardiol 2019 10 2;293:45-47. Epub 2019 Jul 2.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2019.06.079DOI Listing
October 2019

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure.

Circ Res 2019 06 20;125(1):117-146. Epub 2019 Jun 20.

From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY.

The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.311148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588179PMC
June 2019

How do endosomal Toll-like receptors sense and extend ischaemic myocardial injury?

Cardiovasc Res 2019 10;115(12):1687-1689

Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer G46B, Bronx, NY, USA.

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http://dx.doi.org/10.1093/cvr/cvz128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755353PMC
October 2019

Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation.

Circ Res 2019 06 16;125(1):55-70. Epub 2019 May 16.

From the Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY (B.C., S.H., Y.S., Y-J.W., A.H., A.B., N.G.F.).

Rationale: TGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad pathways. The in vivo role of TGF-β signaling in regulation of macrophage function is poorly understood. We hypothesized that in the infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling.

Objective: To investigate the role of macrophage-specific TGF-β Smad3 signaling in a mouse model of myocardial infarction and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function.

Methods And Results: TGF-βs markedly activated Smad3 in macrophages, without affecting Smad-independent pathways. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β release. MyS3KO (myeloid cell-specific Smad3 knockout) mice had no baseline defects but exhibited increased late mortality and accentuated dilative postmyocardial infarction remodeling. Adverse outcome in infarcted MyS3KO mice was associated with perturbations in phagocytic activity, defective transition of macrophages to an anti-inflammatory phenotype, scar expansion, and accentuated apoptosis of border zone cardiomyocytes. In vitro, Smad3 null macrophages exhibited reduced expression of genes associated with eat-me signals, such as Mfge8 (milk fat globule-epidermal growth factor factor 8), and reduced capacity to produce the anti-inflammatory mediators IL (interleukin)-10 and TGF-β1, and the angiogenic growth factor VEGF (vascular endothelial growth factor). Mfge8 partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Impaired anti-inflammatory actions of Smad3 null macrophages were associated with marked attenuation of phagocytosis-induced PPAR (peroxisome proliferator-activated receptor) expression. MyS3KO mice had no significant alterations in microvascular density and interstitial fibrosis in remodeling myocardial segments.

Conclusions: We demonstrate that Smad3 critically regulates function of infarct macrophages, by mediating acquisition of a phagocytic phenotype and by contributing to anti-inflammatory transition. Smad3-dependent actions in macrophages protect the infarcted heart from adverse remodeling.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681442PMC
June 2019

Distinct roles of myofibroblast-specific Smad2 and Smad3 signaling in repair and remodeling of the infarcted heart.

J Mol Cell Cardiol 2019 07 11;132:84-97. Epub 2019 May 11.

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America. Electronic address:

TGF-βs regulate fibroblast responses, by activating Smad2 or Smad3 signaling, or via Smad-independent pathways. We have previously demonstrated that myofibroblast-specific Smad3 is critically implicated in repair of the infarcted heart. However, the role of fibroblast Smad2 in myocardial infarction remains unknown. This study investigates the role of myofibroblast-specific Smad2 signaling in myocardial infarction, and explores the mechanisms responsible for the distinct effects of Smad2 and Smad3. In a mouse model of non-reperfused myocardial infarction, Smad2 activation in infarct myofibroblasts peaked 7 days after coronary occlusion. In vitro, TGF-β1, -β2 and -β3, but not angiotensin 2 and bone morphogenetic proteins-2, -4 and -7, activated fibroblast Smad2. Myofibroblast-specific Smad2 and Smad3 knockout mice (FS2KO, FS3KO) and corresponding control littermates underwent non-reperfused infarction. In contrast to the increase in rupture rates and adverse remodeling in FS3KO mice, FS2KO animals had mortality comparable to Smad2 fl/fl controls, and exhibited a modest but transient improvement in dysfunction after 7 days of coronary occlusion. At the 28 day timepoint, FS2KO and Smad2 fl/fl mice had comparable adverse remodeling. Although both FS3KO and FS2KO animals had increased myofibroblast density in the infarct, only FS3KO mice exhibited impaired scar organization, associated with perturbed alignment of infarct myofibroblasts. In vitro, Smad3 but not Smad2 knockdown downmodulated fibroblast α2 and α5 integrin expression. Moreover, Smad3 knockdown reduced expression of the GTPase RhoA, whereas Smad2 knockdown markedly increased fibroblast RhoA levels. Smad3-dependent integrin expression may be important for fibroblast activation, whereas RhoA may transduce planar cell polarity pathway signals, essential for fibroblast alignment. Myofibroblast-specific Smad3, but not Smad2 is required for formation of aligned myofibroblast arrays in the infarct. The distinct in vivo effects of myofibroblast Smad2 and Smad3 may involve Smad3-dependent integrin synthesis, and contrasting effects of Smad2 and Smad3 on RhoA expression.
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http://dx.doi.org/10.1016/j.yjmcc.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579679PMC
July 2019

Can Myocardial Fibrosis Be Reversed?

J Am Coll Cardiol 2019 05;73(18):2283-2285

The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, New York. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2018.10.094DOI Listing
May 2019

Pericytes in the infarcted heart.

Vasc Biol 2019 25;1(1):H23-H31. Epub 2019 Apr 25.

Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, USA.

The adult mammalian heart lacks regenerative capacity and heals through activation of an inflammatory cascade that leads to the formation of a collagen-based scar. Although scar formation is important to preserve the structural integrity of the ventricle, unrestrained inflammation and excessive fibrosis have been implicated in the pathogenesis of adverse post-infarction remodeling and heart failure. Interstitial cells play a crucial role in the regulation of cardiac repair. Although recent studies have explored the role of fibroblasts and immune cells, the cardiac pericytes have been largely ignored by investigators interested in myocardial biology. This review manuscript discusses the role of pericytes in the regulation of inflammation, fibrosis and angiogenesis following myocardial infarction. During the inflammatory phase of infarct healing, pericytes may regulate microvascular permeability and may play an important role in leukocyte trafficking. Moreover, pericyte activation through Toll-like receptor-mediated pathways may stimulate cytokine and chemokine synthesis. During the proliferative phase, pericytes may be involved in angiogenesis and fibrosis. To what extent pericyte to fibroblast conversion and pericyte-mediated growth factor synthesis contribute to the myocardial fibrotic response remains unknown. During the maturation phase of infarct healing, coating of infarct neovessels with pericytes plays an important role in scar stabilization. Implementation of therapeutic approaches targeting pericytes in the infarcted and remodeling heart remains challenging, due to the lack of systematic characterization of myocardial pericytes, their phenotypic heterogeneity and the limited knowledge on their functional role.
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http://dx.doi.org/10.1530/VB-19-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439839PMC
April 2019

Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities.

Cardiovasc Res 2019 06;115(7):1117-1130

Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore.

New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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http://dx.doi.org/10.1093/cvr/cvz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529904PMC
June 2019
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