Dataset Information

CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

ABSTRACT:

Background and purpose

Previous studies of ischemia-reperfusion injury (IRI) in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2) would limit infarct size and improve functional recovery and what signaling pathways are involved.

Experimental approach

Isolated mice hearts were perfused ad modum Langendorff, subjected to no-flow, global ischemia, and subsequently, exposed to mammalian cell derived, full-length (38-40kDa) rhCCN2 (250 nM) or vehicle during the first 15 min of a 60 min reperfusion period.

Key results

Post-ischemic administration of rhCCN2 resulted in attenuation of infarct size from 58 ± 4% to 34 ± 2% (p < 0.001) which was abrogated by concomitant administration of the PI3 kinase inhibitor LY294002 (45 ± 3% vs. 50 ± 3%, ns). In congruence with reduction of infarct size rhCCN2 also improved recovery of left ventricular developed pressure (p < 0.05). Western blot analyses of extracts of ex vivo-perfused murine hearts also revealed that rhCCN2 evoked concentration-dependent increase of cardiac phospho-GSK3? (serine-9) contents.

Conclusions and implications

We demonstrate that post-ischemic administration of rhCCN2 increases the tolerance of ex vivo-perfused murine hearts to IRI. Mechanistically, this postconditioning effect of rhCCN2 appeared to be mediated by activation of the reperfusion injury salvage kinase pathway as demonstrated by sensitivity to PI3 kinase inhibition and increased CCN2-induced phosphorylation of GSK3? (Ser-9). Thus, the rationale for testing rhCCN2-mediated post-ischemic conditioning of the heart in more complex models is established.

SUBMITTER: Kaasboll OJ

PROVIDER: S-EPMC4752337 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

Kaasbøll Ole Jørgen OJ Moe Ingvild Tronstad IT Ahmed Mohammad Shakil MS Stang Espen E Hagelin Else Marie Valbjørn EM Attramadal Håvard H

PloS one 20160212 2

<h4>Background and purpose</h4>Previous studies of ischemia-reperfusion injury (IRI) in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2) would limit infarct size and improve functional recovery and what signaling pathways are involved.<h4>Experimental approach</h4>Isolated mice hearts were perfused ad ...[more]

PMID: 26872261

Similar Datasets

Project description:TGF-β2 is the predominant TGF-β isoform within the eye. One function of TGF-β2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-β2 within the eye must be under tight control of a network of different factors. A disbalance of the network can result in different eye diseases. In Primary Open-Angle Glaucoma (POAG), one of the leading causes of irreversible blindness worldwide, TGF-β2 is significantly elevated in the aqueous humor and antagonistic molecules like BMPs are reduced. The changes provoke an altering of the quantity and quality of the extracellular matrix and the actin cytoskeleton in the outflow tissues, leading to an increased outflow resistance and thereby to an increased intraocular pressure (IOP), the major risk factor for primary open-angle glaucoma. The pathologic effect of TGF-β2 in primary open-angle glaucoma is mainly meditated by CCN2/CTGF. CCN2/CTGF can modulate TGF-β and BMP signaling by direct binding. The eye specific overexpression of CCN2/CTGF caused an increase in IOP and led to a loss of axons, the hallmark of primary open-angle glaucoma. CCN2/CTGF appears to play a critical role in the homeostatic balance of the eye, so we investigated if CCN2/CTGF can modulate BMP and TGF-β signaling pathways in the outflow tissues. To this end, we analyzed the direct effect of CCN2/CTGF on both signaling pathways in two transgenic mouse models with a moderate (βB1-CTGF1) and a high CCN2/CTGF (βB1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2/CTGF mediates TGF-β effects via different pathways. We observed developmental malformations in the ciliary body in βB1-CTGF6 caused by an inhibition of the BMP signaling pathway. In βB1-CTGF1, we detected a dysregulation of the BMP and TGF-β signaling pathways, with reduced BMP activity and increased TGF-β signaling. A direct CCN2/CTGF effect on BMP and TGF-β signaling was shown in immortalized HTM cells. Finally, CCN2/CTGF mediated its effects on TGF-β via the RhoA/ROCK and ERK signaling in immortalized HTM cells. We conclude that CCN2/CTGF functions as a modulator of the homeostatic balance of BMP and TGF-β signaling pathways, which is shifted in primary open-angle glaucoma.

Dataset Information

CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets