Differential and combined effects of cardiotrophin-1 and TGF-β<sub>1</sub>on cardiac myofibroblast proliferation and contraction

Drobic, Vanja; Cunnington, Ryan H.; Bedosky, Kristen M.; Raizman, Joshua E.; Elimban, Vinit V; Rattan, Sunil G.; Dixon, Ian M.C.

doi:10.1152/ajpheart.00935.2006

Cited by 35 publications

(23 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the cumulative CTGF protein level as determined by western blotting was clearly enhanced 6-fold by TGFβ1 treatment. Moreover, TGFβ1 induced a small but statistically significant enhancement of collagen gel contraction, as was described previously (Drobic et al, 2007).…”

Section: Accepted M Manuscriptsupporting

confidence: 84%

“…Studies with isolated CF show that TGFβ1 induces differentiation of CF to CMF (Swaney et al, 2005), and stimulates collagen production (Butt et al, 1995;Chua et al, 1991;Eghbali et al, 1991;Lijnen et al, 2000;Swaney et al, 2005). In addition, TGFβ1 enhances in vitro collagen gel contraction by CF (Burgess et al, 1994;Drobic et al, 2007;Lijnen et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

et al. 2013

View full text Add to dashboard Cite

A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractDuring cardiac remodeling, cardiac fibroblasts (CF) are influenced by increased levels of interleukin-1α (IL-1α) and transforming growth factor-β1 (TGFβ1). The present study investigated the interaction between these two important cytokines on function of human CF and their differentiation to myofibroblasts (CMF). CF were isolated from human atrial appendage and exposed to IL-1α and/or TGFβ1 (both 0.1 ng/ml). mRNA expression levels of selected genes were determined after 6-24 h by real-time RT-PCR, while protein levels were analyzed at 24-48 h by ELISA or Western blot.Activation of canonical signaling pathways (NFB, Smad3, p38 MAPK) was determined by Western blotting. Differentiation to CMF was examined by collagen gel contraction assays. Exposure of CF to IL-1α alone enhanced levels of IL-6, IL-8, matrix metalloproteinase-3 (MMP3) and collagen III (COL3A1), but reduced the CMF markers α-smooth muscle actin (αSMA) and connective tissue growth factor (CTGF/CCN2). By contrast, TGFβ1 alone had minor effects on IL-6, IL-8 and MMP3levels, but significantly increased levels of the CMF markers αSMA, CTGF, COL1A1 and COL3A1.Co-stimulation with both IL-1α and TGFβ1 increased MMP3 expression synergistically. Furthermore, while TGFβ1 had no effect on IL-1α-induced IL-6 or IL-8 levels, co-stimulation inhibited the TGFβ1-induced increase in αSMA and blocked the gel contraction caused by TGFβ1. Combining IL-1α and TGFβ1 had no apparent effect on their canonical signaling pathways. In conclusion, IL-1α and TGFβ1 act synergistically to stimulate MMP3 expression in CF. Moreover, IL-1α has a dominant inhibitory effect on the phenotypic switch of CF to CMF induced by TGFβ1.

show abstract

Section: Accepted M Manuscriptsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

et al. 2013

View full text Add to dashboard Cite

show abstract

“…This inhibition was prevented by pretreatment of the cells with the PKC inhibitor bisindolylmaleimide I, suggesting that current reduction is mediated by PKC. Although PKC-mediated phosphorylation is known to stimulate neonatal cardiac fibroblast proliferation and adhesion (3,7,17), this is the first study to demonstrate a regulatory action of PKC on ion channels in these cells.…”

Section: Expression Of Kv Channels In Neonatal Rat Cardiac Fibroblastsmentioning

confidence: 81%

Neonatal rat cardiac fibroblasts express three types of voltage-gated K⁺ channels: regulation of a transient outward current by protein kinase C

Walsh¹,

Zhang²

2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Walsh KB, Zhang J. Neonatal rat cardiac fibroblasts express three types of voltage-gated K ϩ channels: regulation of a transient outward current by protein kinase C. Am J Physiol Heart Circ Physiol 294: H1010-H1017, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01195.2007.-Cardiac fibroblasts regulate myocardial development via mechanical, chemical, and electrical interactions with associated cardiomyocytes. The goal of this study was to identify and characterize voltage-gated K ϩ (Kv) channels in neonatal rat ventricular fibroblasts. With the use of the whole cell arrangement of the patch-clamp technique, three types of voltagegated, outward K ϩ currents were measured in the cultured fibroblasts. The majority of cells expressed a transient outward K ϩ current (Ito) that activated at potentials positive to Ϫ40 mV and partially inactivated during depolarizing voltage steps. Ito was inhibited by the antiarrhythmic agent flecainide (100 M) and BaCl2 (1 mM) but was unaffected by 4-aminopyridine (4-AP; 0.5 and 1 mM). A smaller number of cells expressed one of two types of kinetically distinct, delayed-rectifier K ϩ currents [IK fast (IKf) and IK slow (IKs)] that were strongly blocked by 4-AP. Application of phorbol 12-myristate 13-acetate, to stimulate protein kinase C (PKC), inhibited Ito but had no effect on IKf and IKs. Immunoblot analysis revealed the presence of Kv1.4, Kv1.2, Kv1.5, and Kv2.1 ␣-subunits but not Kv4.2 or Kv1.6 ␣-subunits in the fibroblasts. Finally, pretreatment of the cells with 4-AP inhibited angiotensin II-induced intracellular Ca 2ϩ mobilization. Thus neonatal cardiac fibroblasts express at least three different Kv channels that may contribute to electrical/chemical signaling in these cells. cardiac fibroblasts DEVELOPMENT OF THE VERTEBRATE myocardium requires the interaction of several cell types, including myocytes, fibroblasts, smooth muscle cells, and endothelial cells (2, 3). Although cardiac myocytes make up the bulk of the myocardial volume, the cardiac fibroblast is the most numerous cell type found in the heart and functions in the deposition of the extracellular matrix (2, 3). In addition, fibroblasts can serve as "sentinel cells" that coordinate the myocardial response to chemical and mechanical stimulation through the release of cytokines and growth factors (2,3,15). Release of these signals during myocardial injury may regulate the extent of cardiac hypertrophy and fibrosis during the healing process (5, 15).Recent experiments suggest that cardiac fibroblasts also serve to relay electrical signals in the heart. When plated in primary culture, cardiac fibroblasts form physical interactions with cardiac myocytes through establishment of gap-junctional channels (6,8,14). With the use of a heterocellular culture model, it was established that fibroblasts are capable of relaying electrical excitation over distances as long as 300 m between strands of cardiac myocytes (14). However, the ionic mechanisms responsible for this electrical propagation are not well understoo...

show abstract

“…The contraction of ECM by cardiac myofibroblasts is an important process in wound healing, and can be studied in vitro by culturing cells in 3D collagen gels. Both Ang II and TGF enhance in vitro collagen gel contraction by CF (Burgess et al, 1994;Drobic et al, 2007;Lijnen et al, 2003).…”

Section: Effect Of Profibrotic Stimuli On Cfmentioning

confidence: 99%

“…TGF1 was also reported to prevent CF proliferation in response to the IL-6 family cytokine cardiotrophin-1 (CT-1) (Drobic et al, 2007). TGF1 and CT-1 had opposing effects when tested individually, but in combination TGF1-mediated effects superseded those of CT-1.…”

Section: Interaction Between Proinflammatory and Profibrotic Stimulimentioning

confidence: 99%

The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

Nieuwenhoven

Turner

2013

Vascular Pharmacology

123

108

View full text Add to dashboard Cite

Cardiac fibroblasts (CF) play a pivotal role in the repair and remodeling of the heart that occurs following myocardial infarction (MI). The transition through the inflammatory, granulation and maturation phases of infarct healing is driven by cellular responses to local levels of cytokines, chemokines and growth factors that fluctuate in a temporal and spatial manner. In the acute inflammatory phase early after MI, CF contribute to the inflammatory milieu through increased secretion of proinflammatory cytokines and chemokines, and they promote extracellular matrix (ECM) degradation by increasing matrix metalloproteinase (MMP) expression and activity. In the granulation phase, CF migrate into the infarct zone, proliferate and produce MMPs and pro-angiogenic molecules to facilitate revascularization.Fibroblasts also undergo a phenotypic change to become myofibroblasts. In the maturation phase, inflammation is reduced by anti-inflammatory cytokines, and increased levels of profibrotic stimuli induce myofibroblasts to synthesize new ECM to form a scar. The scar is contracted through the mechanical force generated by myofibroblasts, preventing cardiac dilation. In this review we discuss the transition from myocardial inflammation to fibrosis with particular focus on how CF respond to alterations in proinflammatory and profibrotic signals. By furthering our understanding of these events, it is hoped that new therapeutic interventions will be developed that selectively reduce adverse myocardial remodeling post-MI, whilst sparing essential repair mechanisms.

show abstract

Differential and combined effects of cardiotrophin-1 and TGF-β₁on cardiac myofibroblast proliferation and contraction

Cited by 35 publications

References 59 publications

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

Neonatal rat cardiac fibroblasts express three types of voltage-gated K⁺ channels: regulation of a transient outward current by protein kinase C

The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

Contact Info

Product

Resources

About

Differential and combined effects of cardiotrophin-1 and TGF-β1on cardiac myofibroblast proliferation and contraction

Cited by 35 publications

References 59 publications

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

Neonatal rat cardiac fibroblasts express three types of voltage-gated K+ channels: regulation of a transient outward current by protein kinase C

The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

Contact Info

Product

Resources

About

Differential and combined effects of cardiotrophin-1 and TGF-β₁on cardiac myofibroblast proliferation and contraction

Neonatal rat cardiac fibroblasts express three types of voltage-gated K⁺ channels: regulation of a transient outward current by protein kinase C