The action of mimetic peptides on connexins protects fibroblasts from the negative effects of ischemia reperfusion

Glass, Beverley J.; Hu, Rebecca; Phillips, Anthony R. J.; Becker, David L.

doi:10.1242/bio.013573

Cited by 14 publications

(10 citation statements)

References 46 publications

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“…A similar effect was also observed in adult human gingival fibroblasts where Gap27 also enhanced wound closure rates [ 29 ]. Studies using mouse NIH3T3 fibroblasts also determined that Gap27 reduced Cx43 protein expression in line with our observations in JFF cells [ 43 ]. Studies in our lab also determined that Gap27 improved cell migration rates in primary neonatal mouse fibroblasts [ 27 ] and keratinocytes [ 44 ].…”

Section: Discussionsupporting

confidence: 88%

The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems

Faniku

O'Shaughnessy

Lorraine

et al. 2018

IJMS

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In the epidermis, remodelling of Connexin43 is a key event in wound closure. However, controversy between the role of connexin channel and non-channel functions exist. We compared the impact of SiRNA targeted to Connexin43 and the connexin mimetic peptide Gap27 on scrape wound closure rates and hemichannel signalling in adult keratinocytes (AK) and fibroblasts sourced from juvenile foreskin (JFF), human neonatal fibroblasts (HNDF) and adult dermal tissue (ADF). The impact of these agents, following 24 h exposure, on GJA1 (encoding Connexin43), Ki67 and TGF-β1 gene expression, and Connexin43 and pSmad3 protein expression levels, were examined by qPCR and Western Blot respectively. In all cell types Gap27 (100 nM–100 μM) attenuated hemichannel activity. In AK and JFF cells, Gap27 (100 nM–100 μM) enhanced scrape wound closure rates by ~50% but did not influence movement in HNDF or ADF cells. In both JF and AK cells, exposure to Gap27 for 24 h reduced the level of Cx43 protein expression but did not affect the level in ADF and HNDF cells. Connexin43-SiRNA enhanced scrape wound closure in all the cell types under investigation. In HDNF and ADF, Connexin43-SiRNA enhanced cell proliferation rates, with enhanced proliferation also observed following exposure of HDNF to Gap27. By contrast, in JFF and AK cells no changes in proliferation occurred. In JFF cells, Connexin43-SiRNA enhanced TGF-β1 levels and in JFF and ADF cells both Connexin43-SiRNA and Gap27 enhanced pSmad3 protein expression levels. We conclude that Connexin43 signalling plays an important role in cell migration in keratinocytes and foreskin derived fibroblasts, however, different pathways are evoked and in dermal derived adult and neonatal fibroblasts, inhibition of Connexin43 signalling plays a more significant role in regulating cell proliferation than cell migration.

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Section: Discussionsupporting

confidence: 88%

The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems

Faniku

O'Shaughnessy

Lorraine

et al. 2018

IJMS

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“…FRAP assay was performed to characterize the inhibitory effect of Gap 26 in gap junction‐based intercellular communication . Fibroblasts were initially incubated with Gap26 before calcein staining.…”

Section: Resultsmentioning

confidence: 99%

“…FRAP assay was performed to characterize the inhibitory effect of Gap 26 in gap junction-based intercellular communication. 33 Fibroblasts were initially incubated with Gap26 before calcein staining. Subsequently, selected area of the cells was photobleached using high Subsequently, we loaded PEGDA microneedles with Gap26 through the swelling effect of PEGDA.…”

Section: Peptide Loaded Pegda Microneedlesmentioning

confidence: 99%

Peptide delivery with poly(ethylene glycol) diacrylate microneedles through swelling effect

Liu

Yeo

Wiraja

et al. 2017

Bioengineering & Transla Med

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Transdermal delivery of therapeutic biomolecules (including peptides) can avoid enzymatic digestion that occurs in the oral route. (Polyethylene glycol) diacrylate (PEGDA)‐based microneedles, with good biocompatibility, are easily fabricated through photo‐polymerization with a precisely controlled structure. It has successfully been used for the transdermal delivery of small molecule drugs such as 5‐fluorouracil. However, the delivery of peptide‐based therapeutics using this platform is seldom reported. This is because of the potential damage to the peptide during the photo‐polymerization process of PEGDA. Herein, we introduce a method to load PEGDA microneedles with peptides without compromising peptide potency. Using gap junction inhibitor (Gap 26) as an example, the peptide was loaded into PEGDA microneedles through the swelling effect of PEGDA in the aqueous solution. The peptide‐loaded microneedles were applied to a keloid scar model and exhibited inhibition expression of collagen I, a predominant marker of keloid scar, demonstrating its potential therapeutic effects.

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“…37,43 Gap27 has previously been shown to have an IC 50 of 31.5 ± 4.1 µM and to produce a maximum effect at 100 µM [ 69 ]. We previously used 37,43 Gap27 at 100 µM [ 70 , 71 , 72 ]. In another subset of relaxation experiments, the l- NAME (100 µM) was used to inhibit eNOS.…”

Section: Methodsmentioning

confidence: 99%

Connexin 43 Plays a Role in Pulmonary Vascular Reactivity in Mice

Htet

Nally

Shaw

et al. 2018

IJMS

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Pulmonary arterial hypertension (PAH) is a chronic condition characterized by vascular remodeling and increased vaso-reactivity. PAH is more common in females than in males (~3:1). Connexin (Cx)43 has been shown to be involved in cellular communication within the pulmonary vasculature. Therefore, we investigated the role of Cx43 in pulmonary vascular reactivity using Cx43 heterozygous (Cx43+/−) mice and 37,43Gap27, which is a pharmacological inhibitor of Cx37 and Cx43. Contraction and relaxation responses were studied in intra-lobar pulmonary arteries (IPAs) derived from normoxic mice and hypoxic mice using wire myography. IPAs from male Cx43+/− mice displayed a small but significant increase in the contractile response to endothelin-1 (but not 5-hydroxytryptamine) under both normoxic and hypoxic conditions. There was no difference in the contractile response to endothelin-1 (ET-1) or 5-hydroxytryptamine (5-HT) in IPAs derived from female Cx43+/−mice compared to wildtype mice. Relaxation responses to methacholine (MCh) were attenuated in IPAs from male and female Cx43+/− mice or by pre-incubation of IPAs with 37,43Gap27. Nω-Nitro-L-arginine methyl ester (l-NAME) fully inhibited MCh-induced relaxation. In conclusion, Cx43 is involved in nitric oxide (NO)-induced pulmonary vascular relaxation and plays a gender-specific and agonist-specific role in pulmonary vascular contractility. Therefore, reduced Cx43 signaling may contribute to pulmonary vascular dysfunction.

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The action of mimetic peptides on connexins protects fibroblasts from the negative effects of ischemia reperfusion

Cited by 14 publications

References 46 publications

The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems

The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems

Peptide delivery with poly(ethylene glycol) diacrylate microneedles through swelling effect

Connexin 43 Plays a Role in Pulmonary Vascular Reactivity in Mice

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