FK506 can activate transforming growth factor-  signalling in vascular smooth muscle cells and promote proliferation

Giordano, Arturo; Romano, Simona; Mallardo, Maria; Dilhas, Anna; Calı̀, Gaetano; Corcione, Nicola; Ferraro, Paolo; Romano, Maria

doi:10.1093/cvr/cvn079

Cited by 39 publications

(40 citation statements)

References 40 publications

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“…As shown in Fig. 4, top row, cells without FK506 treatment show a certain degree of ALK1/FKBP12 colocalization, a similar result as reported by Giordano et al (2008), in vascular smooth muscle cells with FKBP12 and the ubiquitous type I receptor ALK5. As shown by these authors, FKBP12 is an inhibitor of TGF-␤1 receptor type I ALK5 in myoblasts.…”

Section: Fk506 Increases Endoglin and Alk1 Expression 837supporting

confidence: 86%

“…In particular, FKBP12 is a natural inhibitor of TGF-␤1-mediated signaling; therefore, ligands, such as FK506, act as TGF-␤1 activators, competing with the FKBP12 for the TGF-␤1 receptors (Udina and Navarro, 2002). In fact, in a previous report, Giordano et al (2008) demonstrated that FK506 increases the phosphorylation of Smad2/3, sequestering FKBP12, a receptor type I inhibitor, in mouse VSMCs. In this work, we have described the action of FK506 in endothelial cells, in which it triggers activation through the endothelial-specific receptor type I, ALK1/Smad1/5/8, as demonstrated by ALK1-specific reporter activation of this pathway (BRE-luc), and the natural promoter regulated by this way, Id1.…”

Section: Fk506 Increases Endoglin and Alk1 Expression 841mentioning

confidence: 92%

“…Giordano et al, (2008) have shown how FK506 can activate the TGF-␤1/ALK5 pathway in vascular smooth muscle cells (VSMCs) by increasing the phosphorylation of Smad 2/3. This effect was explained by the binding of FK506 to the nucleophilin FKBP12, a TGF-␤1 receptor type I inhibitor.…”

Section: Fk506 Increases Alk1 and Endoglin Protein Levelsmentioning

confidence: 99%

“…This differential behavior is explained by the type of TGF-␤1 receptors involved. Whereas in VSMCs, the activation is through the TGF-␤1/ALK5 pathway (Giordano et al, 2008), in endothelial cells, FK506 acts through the endothelial-specific receptor type I, ALK1. Thus, according to Fig.…”

Section: Fk506 Increases Endoglin and Alk1 Expression 837mentioning

confidence: 99%

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Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Albiñana¹,

Sanz-Rodrı́guez²,

Recio-Poveda³

et al. 2011

Mol Pharmacol

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Hereditary hemorrhagic telangiectasia (HHT), or Rendu-OslerWeber syndrome, is an autosomal-dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in internal organs. Patients show severe epistaxis, and/or gastrointestinal bleeding, both of which notably interfere with their quality of life. There are two predominant types of HHT caused by mutations in endoglin (ENG) and ACVRL1/activin receptor-like kinase 1 (ALK1) genes, named HHT1 and HHT2, respectively. ENG and ALK1 code for proteins involved in the transforming growth factor (TGF)-␤1 signaling pathway, and it is widely accepted that HHT pathogenicity results from haploinsufficiency. No cure for HHT has been found, so identification of drugs able to increase the expression of these genes is essential when proposing new therapies. We report the efficacy of tacrolimus (FK506) in increasing ENG and ALK1 expression. The rationale comes from a case report of a patient with HHT who received a liver transplantation after hepatic failure due to a liver arteriovenous malformation. The liver was transplanted, and the immunosuppressor FK506 was used to prevent the rejection. After the first month of FK506 treatment, the internal and external telangiectases, epistaxes, and anemia disappeared. Here, we find that the immunosuppressor FK506 increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells and enhances the TGF-␤1/ALK1 signaling pathway and endothelial cell functions like tubulogenesis and migration. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haploinsufficiency and may therefore be an interesting drug for use in patients with HHT who undergo transplantation.

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Section: Fk506 Increases Endoglin and Alk1 Expression 837supporting

confidence: 86%

Section: Fk506 Increases Endoglin and Alk1 Expression 841mentioning

confidence: 92%

Section: Fk506 Increases Alk1 and Endoglin Protein Levelsmentioning

confidence: 99%

Section: Fk506 Increases Endoglin and Alk1 Expression 837mentioning

confidence: 99%

See 2 more Smart Citations

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Albiñana¹,

Sanz-Rodrı́guez²,

Recio-Poveda³

et al. 2011

Mol Pharmacol

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“…Rapamycin induces VSMC differentiation by specific activation of the Akt2 isoform, promoting expression of contractile proteins (129). In fact, arachidonic acid, TGF-β, FK506, and leptin induce VSMC proliferation through PI3K-dependent activation of mTOR (130)(131)(132)(133). Thus, autophagy in VSMCs can confer both adaptive and maladaptive actions depending on the context.…”

Section: Autophagy In Vascular Remodelingmentioning

confidence: 99%

Autophagy in cardiovascular biology

Lavandero

Chiong

Rothermel³

et al. 2015

J. Clin. Invest.

286

211

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Autophagy in the vascular systemEndothelial cells. Autophagy can be regulated in vascular endothelial cells by compounds circulating in the bloodstream or localized within the subendothelial layer of atherosclerotic plaque. For example, in cultured HUVECs, vitamin D increases beclin 1, a key comCardiovascular disease is the leading cause of death worldwide. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been widely characterized in cardiomyocytes, cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, and macrophages. In all cases, a window of optimal autophagic activity appears to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. In this Review, we discuss the potential for targeting autophagy therapeutically and our vision for where this exciting biology may lead in the future.

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Toxoplasma gondii Dense Granule Antigen 1 stimulates apoptosis of monocytes through autocrine TGF-β signaling

et al. 2011

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Monocyte/macrophages represent the first line of defense against protozoan parasites. Different mechanisms of monocyte suppression by Toxoplasma gondii that sustain parasite invasion and persistence have been described, including apoptosis. In the present study, we investigated the effect of microbial excretory–secretory polypeptides, namely the microneme protein MIC3 and the dense granule antigen GRA1, on apoptosis of monocytes from patients with congenital toxoplasmosis and healthy individuals. We found that GRA1 but not MIC3 could induce apoptosis of monocytes, observing the effect in samples from both Toxoplasma-infected and uninfected individuals, thus ruling out involvement of mechanisms of apoptosis linked to adaptive immunity or a cellular context related to infection. Selective inhibition of TGF-β type I receptors reversed GRA1-induced apoptosis, indicating that this apoptosis involved canonical TGF-β signaling. By using TGF-β-neutralizing antibodies, we showed that monocyte apoptosis required endogenous TGF-β and that GRA1 stimulation activated TGF-β transcription and expression in monocytes but not lymphocytes, suggesting involvement of an autocrine TGF-β-mediated mechanism in GRA1-induced apoptosis.

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FK506 can activate transforming growth factor- signalling in vascular smooth muscle cells and promote proliferation

Abstract: FK506 can act as a growth factor for VSMCs.

Cited by 39 publications

References 40 publications

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Autophagy in cardiovascular biology

Toxoplasma gondii Dense Granule Antigen 1 stimulates apoptosis of monocytes through autocrine TGF-β signaling

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