Stimulation of Collagen Production by Transforming Growth Factor-β
            <sub>1</sub>
            During Differentiation of Cardiac Fibroblasts to Myofibroblasts

Petrov, Victor; Fagard, Robert; Lijnen, Paul

doi:10.1161/hy0202.103268

Cited by 383 publications

(283 citation statements)

References 30 publications

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“…This is surprising given that our previous work showed TGF-␤3 to be the least potent inducer of scleral collagen production (16), and there is a high correlation between myofibroblast differentiation (i.e. increased ␣-SMA) and increased collagen production (34,35). TGF-␤3 is generally found to be involved in the organized remodeling of ECM rather than the relatively disorganized fibrotic process of myofibroblast-mediated ECM production (36).…”

Section: Discussionmentioning

confidence: 91%

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Jobling

Gentle

Metlapally

et al. 2009

Journal of Biological Chemistry

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Reduced extracellular matrix accumulation in the sclera of myopic eyes leads to increased ocular extensibility and is related to reduced levels of scleral transforming growth factor-␤ (TGF-␤). The current study investigated the impact of this extracellular environment on scleral cell phenotype and cellular biomechanical characteristics. Scleral cell phenotype was investigated in vivo in a mammalian model of myopia using the myofibroblast marker, ␣-smooth muscle actin (␣-SMA). In eyes developing myopia ␣-SMA levels were increased, suggesting increased numbers of contractile myofibroblasts, and decreased in eyes recovering from myopia. To understand the factors regulating this change in scleral phenotype, the competing roles of TGF-␤ and mechanical stress were investigated in scleral cells cultured in three-dimensional collagen gels. All three mammalian isoforms of TGF-␤ altered scleral cell phenotype to produce highly contractile, ␣-SMA-expressing myofibroblasts (TGF-␤3 > TGF-␤2 > TGF-␤1). Exposure of cells to the reduced levels of TGF-␤ found in the sclera in myopia produced decreased cellmediated contraction and reduced ␣-SMA expression. These findings are contrary to the in vivo gene expression data. However, when cells were exposed to both the increased stress and the reduced levels of TGF-␤ found in myopia, increased ␣-SMA expression was observed, replicating in vivo findings. These results show that although reduced scleral TGF-␤ is a major contributor to the extracellular matrix remodeling in the myopic eye, it is the resulting increase in scleral stress that dominates the competing TGF-␤ effect, inducing increased ␣-SMA expression and, hence, producing a larger population of contractile cells in the myopic eye.

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Section: Discussionmentioning

confidence: 91%

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Jobling

Gentle

Metlapally

et al. 2009

Journal of Biological Chemistry

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“…139,140 Its levels are highly upregulated during heart failure progression. 139 Upon activation, TGF-β1 binds to its type II receptor which propagates downstream intracellular signaling through the small mothers against decapentaplegic (SMAD) proteins and activates transcriptional responses.…”

Section: Myofibroblasts and Tgf-β1mentioning

confidence: 99%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan‐4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan‐4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide through the toll‐like receptor‐4, induced syndecan‐4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor‐κB transcription factor in the syndecan‐4 promoter, and nuclear factor‐κB regulated syndecan‐4 mRNA in cardiac cells. Interestingly, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide induced nuclear factor‐κB‐dependent shedding of the syndecan‐4 ectodomain from cardiac cells. Overexpression of syndecan‐4 with mutated enzyme‐interacting domains suggested enzyme‐dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation‐induced shedding affects function. After aortic banding, a time‐dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan‐4 knockout hearts. Finally, syndecan‐4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan‐4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.

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“…1A). Because serum contains multiple hormones and growth factors that might promote collagen synthesis, we examined the effects of forskolin in response to two key profibrotic agents: angiotensin II (Ang II) and TGF-␤, both tested under serum-free conditions (2,24). Forskolin significantly (P Ͻ 0.05) inhibited collagen synthesis in response to both these profibrotic agents, as well as to aldosterone (data not shown), thus showing that an increase in cAMP inhibits collagen formation in response to multiple agents that promote fibrosis ( Fig.…”

Section: Adenylyl Cyclase Activation Inhibits Total Collagen Synthesimentioning

confidence: 99%

Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase

Swaney

Roth

Olson

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

199

179

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Transformation of fibroblasts to myofibroblasts, characterized by expression of ␣-smooth muscle actin (␣-SMA) and production of extracellular matrix (ECM) components, is a key event in connective tissue remodeling. Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by cardiac fibroblasts (CFs) causes fibrosis, myocardial stiffening, and cardiac dysfunction. We tested whether adenylyl cyclase (AC) activation (increased cAMP levels) modulates the transformation of adult rat CF to myofibroblasts, as assessed by immunofluorescent microscopy, immunoblotting, and collagen synthesis. A 24-h incubation of CF with TGF-␤ or angiotensin II increased ␣-SMA expression, which was inhibited by the AC agonist forskolin and a cAMP analog that activates protein kinase A. Treatment with forskolin blunted serum-, TGF-␤-, and angiotensin II-stimulated collagen synthesis. CFs engineered to overexpress type 6 AC had enhanced forskolin-promoted cAMP formation, greater inhibition by forskolin of TGF-␤-stimulated ␣-SMA expression, and a decrease in the EC 50 of forskolin to reduce serum-stimulated collagen synthesis. The AC stimulatory agonist adrenomedullin inhibited collagen synthesis in CF that overexpressed AC6 but not in controls. Thus, AC stimulation blunts collagen synthesis and, in parallel, the transformation of adult rat CF to myofibroblasts. AC overexpression enhances these effects, ''uncovering'' an inhibition by adrenomedullin. These findings implicate cAMP as an inhibitor of ECM formation by means of blockade of the transformation of CF to myofibroblasts and suggest that increasing AC expression, thereby enhancing cAMP generation through stimulation of receptors expressed on CF, could provide a means to attenuate and prevent cardiac fibrosis and its sequelae.cardiac fibroblast ͉ cyclic AMP ͉ extracellular matrix ͉ fibrosis ͉ heart failure

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Stimulation of Collagen Production by Transforming Growth Factor-β ₁ During Differentiation of Cardiac Fibroblasts to Myofibroblasts

Cited by 383 publications

References 30 publications

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase

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Stimulation of Collagen Production by Transforming Growth Factor-β 1 During Differentiation of Cardiac Fibroblasts to Myofibroblasts

Cited by 383 publications

References 30 publications

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase

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Stimulation of Collagen Production by Transforming Growth Factor-β ₁ During Differentiation of Cardiac Fibroblasts to Myofibroblasts