Induction of Cardiac Fibrosis by Transforming Growth Factor-β1

Lijnen, Paul; Petrov, Victor; Fagard, Robert

doi:10.1006/mgme.2000.3032

Cited by 436 publications

(336 citation statements)

References 130 publications

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“…MAPKs are pivotal mediators of the effects of Ang II on tissue structure by increasing TGF‐β1 expression, leading to atrial fibrosis 38, 39, 40. TGF‐β1 is a cytokine that regulates cell proliferation, apoptosis, migration, and synthesis of ECM, such as fibronectin and collagen in the atrium 41, 42. In our DM rabbit model, we found that hyperglycemia enhanced the activation of MAPKs (p38MAPK, ERK, JNK), expression of TGF‐β1 as well as atrial fibrosis, in keeping with findings from our previous study 26…”

Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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BackgroundThere are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes.Methods and ResultsNinety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment.ConclusionsAllopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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“…These results further support the role of TGF␤1 in ECM deposition in the embryonic heart, similar to findings in other tissues. For example, diabetic rodents demonstrate increased TGF␤1 mRNA and ECM deposition in renal glomeruli and myocardium, effects that are neutralized by inhibiting TGF␤1 activity (Yang et al, 1995;Lijnen et al, 2000;Chen et al, 2001;Goldfarb and Ziyadeh, 2001). …”

Section: Discussionmentioning

confidence: 99%

“…Cardiac remodeling in response to disease is characterized by TGF␤1-induced collagen deposition (Booz and Baker, 1995), and TGF␤1 and endothelin-1 released by cardiac fibroblasts mediate cardiomyocyte hypertrophy (Gray et al, 1998). In rat myocardium, anti-TGF␤1 antibodies prevent induction of ECM protein expression and myocardial fibrosis (Lijnen et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Smoak

2004

Developmental Dynamics

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Cardiovascular defects are common in diabetic offspring, but their etiology and pathogenesis are poorly understood. Extracellular matrix accumulates in adult tissues in response to hyperglycemia, and transforming growth factor-beta1 (TGF␤1) likely mediates this effect. The objective of this study was to characterize TGF␤ expression in the organogenesisstage mouse heart and to evaluate TGF␤ and fibronectin expression in embryonic mouse heart exposed to hyperglycemia. Prominent TGF␤1, and minimal TGF␤2 or TGF␤3, protein expression was demonstrated in embryonic day (E) 9.5-E13.5 hearts. Hyperglycemia for 24 hr produced significantly increased fibronectin, slightly increased TGF␤1, and unchanged TGF␤2 or TGF␤3, by immunohistochemistry. Increased TGF␤1 was demonstrated by enzyme-linked immunosorbent assay in embryonic fluid and isolated hearts after hyperglycemia for 24 hr, but not 48 hr. Hyperglycemia increased fibronectin protein and mRNA expression in embryonic hearts after 24 hr, and pericardial injection of TGF␤1 also increased fibronectin mRNA in the embryonic heart. It is proposed that TGF␤1 and fibronectin may play a role in diabetes-induced cardiac dysmorphogenesis.

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“…21 Indeed several studies have demonstrated that TGF-β promotes collagen synthesis and/or deposition in cultured cardiac fibroblasts in vitro. [22][23][24] Moreover, TGF-β antagonism with neutralizing antibodies, soluble TGF-β receptors, and over expression decorin or dominant negative TGF-β receptors has resulted in attenuation of tissue fibrosis can be attenuated in a variety of different tissues including the heart.…”

Section: Tgf-β Signaling and Myocardial Fibrosismentioning

confidence: 99%

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Sakata¹,

Chancey²,

Divakaran³

et al. 2007

Basic Res Cardiol

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The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a proinflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.

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Induction of Cardiac Fibrosis by Transforming Growth Factor-β1

Cited by 436 publications

References 130 publications

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

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