Angiotensin II stimulates the autocrine production of transforming growth factor-β1 in adult rat cardiac fibroblasts

Lee, Ann A.; Dillmann, Wolfgang H.; McCulloch, Andrew D.; Villarreal, Francisco

doi:10.1016/s0022-2828(95)91983-x

Cited by 243 publications

(141 citation statements)

References 33 publications

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“…This observation is compatible with the studies that have shown angiotensin-II upregulates TGF-β1 mRNA and protein in cardiac fibroblasts, myofibroblasts, and cardiomyocytes (15)(16)(17)(18). TGF-β1 is known to increase the synthesis of collagen and decrease its degradation so as to promote increased collagen deposition (15)(16)(17)(18). TGF-β1 also upregulates profibrotic proteins and extracellular matrix (ECM) protein production, and induces differentiation of cardiac fibroblasts into a more active phenotype, myofibroblasts, which produce collagen at twice faster rates than fibroblasts (19,20).…”

Section: Overexpressionsupporting

confidence: 92%

Section: Overexpressionsupporting

confidence: 91%

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Serum transforming growth factor-ß1 as a risk stratifier of sudden cardiac death

Sovari¹,

Morita

Weiss

et al. 2008

Medical Hypotheses

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Sudden cardiac death prematurely claims the lives of some 7 million each year worldwide. It occurs primarily in patients with an underlying structural cardiac abnormality, and regardless of the type of the underlying pathology (heart failure, dilated and hypertrophic cardiomyopathies, myocardial infarction and aging), death is almost always caused by ventricular tachycardia (VT) which rapidly degenerates to ventricular fibrillation (VF). Implantable cardioverter defibrillator is an effective but expensive therapy for preventing SCD, and finding a reasonably specific, sensitive and cost-effective risk stratification tool for patients at high risk of sudden cardiac death will have great clinical utility in preventing premature sudden cardiac death. Increased myocardial fibrosis has been shown to develop in a wide range of cardiac diseases all manifesting increased risk of VT and VF. Clinical and experimental studies attribute a major role for fibrosis in the initiation of VT, VF and sudden cardiac death. Transforming growth factor-beta1 (TGF-beta1) has been shown to promote myocardial tissue fibrosis and perhaps more importantly in cardiac conditions associated with increased myocardial fibrosis are shown to be positively correlated with increased serum levels of TGF-beta1. In the present hypothesis we suggest that monitoring the serum levels of TGF-beta1 may be a cost-effective risk stratifier to identify patients at high risk of sudden cardiac death caused by VT and VF. BACK GROUND AND THE SCOPE OF THE PROBLEMSudden cardiac death (SCD) prematurely claims each year the lives of more than 300,000 Americans (1) and some 7 million worldwide, and is almost always caused by ventricular tachycardia (VT) that rapidly degenerates to ventricular fibrillation (VF) (1).Myocardial tissue electrical heterogeneity and myocardial structural remodeling such as interstitial fibrosis have been traditionally considered to play a major role in promoting activation wave front instabilities (wavebreaks) that degenerate to VF (2-4). Experimental studies have shown that atrial (5) and ventricular (6) fibrosis considerably increase the incidence of atrial fibrillation and VF initiated by triggered activity. At the present there is no reliable pharmacological approach to effectively prevent VT and VF and as such the placement of implantable cardioverter defibrillator (ICD) remains the only effective approach against SCD (4). Identification of non-invasive markers of SCD can be of considerable benefit to reduce premature mortality in high risk patients in a cost-effective manner. MYOCARDIAL FIBROSIS; A NEW TARGET FOR SCD PREVENTIONFibrosis is characterized by increased deposition of collagenous septa forming insulating barriers within bundles of myocardial cells, and increased density of myocardial fibroblasts and their differentiated active phenotype, myofibroblasts. Myocardial fibrosis is a common feature of diverse types of cardiac diseases that are associated with increased risk of VT and VF causing SCD (1). These conditions i...

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Section: Overexpressionsupporting

confidence: 92%

Section: Overexpressionsupporting

confidence: 91%

Serum transforming growth factor-ß1 as a risk stratifier of sudden cardiac death

Sovari¹,

Morita

Weiss

et al. 2008

Medical Hypotheses

View full text Add to dashboard Cite

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“…Others have shown that fibroblasts are involved in mediating the trophic response of the neonatal rat heart to angiotensin II, probably by releasing transforming growth factor- (Kim et al 1995, Lee et al 1995, and the secretory response of the intestine to inflammation by releasing prostaglandins (Berschneider & Powell 1992, Kandil et al 1994. We are currently investigating whether cardiac fibroblasts fulfil a similar role in local thyroid hormone action in the heart, using animal models of experimentally induced hyper-and hypothyroidism.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of thyroid hormones in cultured cardiac fibroblasts of neonatal rats

Heide

Visser²,

Everts³

et al. 2002

Journal of Endocrinology

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We have investigated the potential role of fibroblasts in local thyroid hormone metabolism in neonatal rat heart. Incubation of cardiac fibroblasts with thyroxine (T4) or 3,5,3 -tri-iodothyronine (T3) resulted in the appearance of water-soluble metabolites, whereas incubation of cardiomyocytes under the same conditions did not or did so to a much lesser extent. Time-course studies showed that production is already evident after 1-5 h of exposure and that the process equilibrates after 24-48 h. Analysis of the products revealed both the T4 and the T3 metabolites to be glucuronides. These results were corroborated by the detection of uridine diphosphate (UDP)-glucuronyltransferase activity in cardiac fibroblasts. We found no indication for outer ring deiodination in fibroblasts, cardiomyocytes or heart homogenates.From these results we have concluded that cardiac fibroblasts, but not cardiomyocytes, are able to glucuronidate T4 and T3 and secrete the conjugates. This could play a role in local metabolism, e.g. to protect the heart tissue from high levels of thyroid hormones.

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“…Although several studies have shown that antagonism of angiotensin II signaling results in decreased TGF-b signaling in a variety of tissues, including kidney, lung, skeletal muscle, heart, and aorta (Shihab et al 1997;Sun et al 1998;Lavoie et al 2005;Habashi et al 2006;Yao et al 2006;Cohn et al 2007;Podowski et al 2012), the exact mechanism by which this occurs is not fully understood (Gibbons et al 1992;Stouffer and Owens 1992;Wolf et al 1993Wolf et al , 1999Kagami et al 1994;Lee et al 1995;Campbell and Katwa 1997;Fukuda et al 2000;Boffa et al 2003;Naito et al 2004;RodriguezVita et al 2005;Zhou et al 2006;Chen et al 2013). Suppression of excessive Erk1 and Erk2 MAPK activation with losartan or an inhibitor of MAPK kinase (MAPKK, also known as MEK) has been shown to normalize aortic architecture and aneurysm pathology in MFS mouse models (Habashi et al 2011), indicating that Erk MAPK activation is critical to aneurysm progression.…”

Section: Tgf-b Family Signaling In Connective Tissuesmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Angiotensin II stimulates the autocrine production of transforming growth factor-β1 in adult rat cardiac fibroblasts

Cited by 243 publications

References 33 publications

Serum transforming growth factor-ß1 as a risk stratifier of sudden cardiac death

Serum transforming growth factor-ß1 as a risk stratifier of sudden cardiac death

Metabolism of thyroid hormones in cultured cardiac fibroblasts of neonatal rats

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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