Tissue transglutaminase in the pathogenesis of heart failure

Shinde, Arti V.; Frangogiannis, Nikolaos G.

doi:10.1038/s41418-017-0028-9

Cited by 21 publications

(13 citation statements)

References 17 publications

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“…[56]. Our findings suggest that although non-enzymatic actions of tTG transduce protective signals that preserve myocardial geometry in the remodeling heart [12],[57] the enzymatic effects of tTG contribute to fibrosis and diastolic dysfunction (Figure 9). Considering the availability of effective and selective tTG inhibitors [58],[59], targeting tTG-dependent transamidation may be a promising therapeutic strategy for subsets of HFpEF patients with a prominent fibrotic phenotype.…”

Section: Discussionmentioning

confidence: 90%

Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload

Shinde

Palanski

et al. 2018

Journal of Molecular and Cellular Cardiology

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Tissue transglutaminase (tTG) is a multifunctional protein with a wide range of enzymatic and non-enzymatic functions. We have recently demonstrated that tTG expression is upregulated in the pressure-overloaded myocardium and exerts fibrogenic actions promoting diastolic dysfunction, while preventing chamber dilation. Our current investigation dissects the in vivo and in vitro roles of the enzymatic effects of tTG on fibrotic remodeling in pressure-overloaded myocardium. Using a mouse model of transverse aortic constriction, we demonstrated perivascular and interstitial tTG activation in the remodeling pressure-overloaded heart. tTG inhibition through administration of the selective small molecule tTG inhibitor ERW1041E attenuated left ventricular diastolic dysfunction and reduced cardiomyocyte hypertrophy and interstitial fibrosis in the pressure-overloaded heart, without affecting chamber dimensions and ejection fraction. In vivo, tTG inhibition markedly reduced myocardial collagen mRNA and protein levels and attenuated transcription of fibrosis-associated genes. In contrast, addition of exogenous recombinant tTG to fibroblast-populated collagen pads had no significant effects on collagen transcription, and instead increased synthesis of matrix metalloproteinase (MMP)3 and tissue inhibitor of metalloproteinases (TIMP)1 through transamidase-independent actions. However, enzymatic effects of matrix-bound tTG increased the thickness of pericellular collagen in fibroblast-populated pads. tTG exerts distinct enzymatic and non-enzymatic functions in the remodeling pressure-overloaded heart. The enzymatic effects of tTG are fibrogenic and promote diastolic dysfunction, but do not directly modulate the pro-fibrotic transcriptional program of fibroblasts. Targeting transamidase-dependent actions of tTG may be a promising therapeutic strategy in patients with heart failure and fibrosis-associated diastolic dysfunction.

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Section: Discussionmentioning

confidence: 90%

Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload

Shinde

Palanski

et al. 2018

Journal of Molecular and Cellular Cardiology

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“…The LOX family is the main enzymatic system responsible for cross-linking of extracellular collagen in fibrotic hearts [309][310][311][312][313] ; its members act on specific lysine or hydroxylysine residues, catalysing allysine aldehyde formation, leading to subsequent spontaneous formation of the cross-links. TG2, (also known as tissue transglutaminase) is the highest-expressed member of the transglutaminase family in remodelling hearts [314][315][316] and catalyzes formation of an isopeptide bond between the e-amino group of a lysine and the c-carboxamide group of a glutamine. In addition to its enzymatic effects, TG2 may also regulate fibroblast phenotype through nonenzymatic mechanisms, modulating integrin-dependent responses.…”

Section: Deposition and Cross-linking Of Fibrillar Collagensmentioning

confidence: 99%

Cardiac fibrosis

Frangogiannis

2020

Cardiovascular Research

646

466

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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 TGF-β and PDGFs), cytokines (including TNF-α, IL-1, IL-6, IL-10 and IL-4), and neurohumoral pathways trigger fibrogenic signaling cascades through binding to surface receptors, and activation of downstream signaling cascades. In addition, matricellular macromolecules are deposited in the remodeling 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 manuscript 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 (HFrEF and HFpEF), 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 remodeling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.

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“…The matricellular protein SPARC (secreted protein acidic and rich in cysteine) also contributes to post-synthetic processing of collagen in the pressure-overloaded heart and increases diastolic stiffness 104 Collagen crosslinking plays an important role in regulation of geometric remodeling and dysfunction in the pressure-overloaded heart. Several crosslinking enzymes are upregulated in the remodeling myocardium, including members of the lysyl oxidase (LOX) family 105 , 106 and transglutaminase-2 (TG2, also known as tissue transglutaminase) 107 , 108 . In addition to its transamidase-dependent enzymatic actions, TG2 bind to the ECM and may also act as a signaling molecule modulating fibroblast-mediated MMP and tissue inhibitor of metalloproteinases (TIMP) synthesis through non-enzymatic mechanisms 109 .…”

Section: Ecm Proteins In the Pressure-overloaded Myocardiummentioning

confidence: 99%

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Frangogiannis

2019

Circulation Research

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374

287

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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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Tissue transglutaminase in the pathogenesis of heart failure

Cited by 21 publications

References 17 publications

Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload

Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload

Cardiac fibrosis

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

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