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New targets of urocortin mediated cardioprotection

New targets of urocortin mediated cardioprotection
New targets of urocortin mediated cardioprotection
The urocortin (Ucn) hormones Ucn1 and Ucn2 have previously been shown to confer significant protection from myocardial ischaemia/reperfusion (I/R) injury; however the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of urocortins which underpin their cardioprotective activity, microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of Ucn1 or Ucn2 before the onset of reperfusion resulted in differential regulation of 66 and 141 genes respectively, the majority of which have not been previously been described. Functional analysis demonstrated that urocortin regulated genes were involved in a wide range of biological responses, including cell death (e.g. XIAP), oxidative stress (e.g. Nrf1/Nfe2l1) and metabolism (e.g. AMPK). In addition, both Ucn1 and Ucn2 were found to modulate the expression of a host of genes involved in G-protein coupled receptor (GPCR) signalling including Rac2, Gnb1, AIP1, Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of corticotrophin releasing hormone (CRH) receptors. Moreover, several of these GPCR related genes have previously been shown to be involved in MAPK activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we show that both Ucn1 and Ucn2 significantly reduce free radical damage following myocardial infarction and comparison of the urocortin gene signatures with that of the antioxidant tempol revealed significant overlap. These data uncover novel gene expression changes induced by urocortins which will serve as platform to further understand their mechanism of action in normal physiology and cardioprotection.



69-85
Barry, Sean Pio
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Lawrence, Kevin M.
ff8347b7-930c-4414-beab-65f6d6514b73
McCormick, James
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Soond, Surinder M.
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Hubank, Mike
ce4812f2-faca-42d9-ac80-7b5109698992
Eaton, Simon
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Sivarajah, Ahila
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Scarabelli, Tiziano M.
ac96a777-880e-4e39-9884-f11a0978da35
Knight, Richard A.
da6172f8-cacc-4330-871a-85dea9e893a4
Thiemermann, Christoph
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Latchman, David S.
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Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Stephanou, Anastasis
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Barry, Sean Pio
834fa454-6979-4db3-82e6-4762870b3113
Lawrence, Kevin M.
ff8347b7-930c-4414-beab-65f6d6514b73
McCormick, James
9f5d47a6-87d4-48c3-a952-4133b710bbb1
Soond, Surinder M.
0648b6e0-c770-4e39-92da-8100fd939e0c
Hubank, Mike
ce4812f2-faca-42d9-ac80-7b5109698992
Eaton, Simon
e14103c2-c06a-45e6-87fe-2358a3371283
Sivarajah, Ahila
a4395e4e-f978-478c-934e-5a14f0932727
Scarabelli, Tiziano M.
ac96a777-880e-4e39-9884-f11a0978da35
Knight, Richard A.
da6172f8-cacc-4330-871a-85dea9e893a4
Thiemermann, Christoph
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Latchman, David S.
71e9db7c-9075-4b49-afac-6413085378db
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Stephanou, Anastasis
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Barry, Sean Pio, Lawrence, Kevin M., McCormick, James, Soond, Surinder M., Hubank, Mike, Eaton, Simon, Sivarajah, Ahila, Scarabelli, Tiziano M., Knight, Richard A., Thiemermann, Christoph, Latchman, David S., Townsend, Paul A. and Stephanou, Anastasis (2010) New targets of urocortin mediated cardioprotection. Journal of Molecular Endocrinology, 45 (2), 69-85.

Record type: Article

Abstract

The urocortin (Ucn) hormones Ucn1 and Ucn2 have previously been shown to confer significant protection from myocardial ischaemia/reperfusion (I/R) injury; however the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of urocortins which underpin their cardioprotective activity, microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of Ucn1 or Ucn2 before the onset of reperfusion resulted in differential regulation of 66 and 141 genes respectively, the majority of which have not been previously been described. Functional analysis demonstrated that urocortin regulated genes were involved in a wide range of biological responses, including cell death (e.g. XIAP), oxidative stress (e.g. Nrf1/Nfe2l1) and metabolism (e.g. AMPK). In addition, both Ucn1 and Ucn2 were found to modulate the expression of a host of genes involved in G-protein coupled receptor (GPCR) signalling including Rac2, Gnb1, AIP1, Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of corticotrophin releasing hormone (CRH) receptors. Moreover, several of these GPCR related genes have previously been shown to be involved in MAPK activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we show that both Ucn1 and Ucn2 significantly reduce free radical damage following myocardial infarction and comparison of the urocortin gene signatures with that of the antioxidant tempol revealed significant overlap. These data uncover novel gene expression changes induced by urocortins which will serve as platform to further understand their mechanism of action in normal physiology and cardioprotection.



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More information

Accepted/In Press date: 25 May 2010
Published date: August 2010
Additional Information: Accepted preprint first posted online on 25 May 2010

Identifiers

Local EPrints ID: 155709
URI: https://eprints.soton.ac.uk/id/eprint/155709
PURE UUID: 24c1eb8b-48e4-4359-a7f7-03a275ff04ed

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Date deposited: 28 May 2010 11:31
Last modified: 05 Nov 2017 12:52

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Contributors

Author: Sean Pio Barry
Author: Kevin M. Lawrence
Author: James McCormick
Author: Surinder M. Soond
Author: Mike Hubank
Author: Simon Eaton
Author: Ahila Sivarajah
Author: Tiziano M. Scarabelli
Author: Richard A. Knight
Author: Christoph Thiemermann
Author: David S. Latchman
Author: Paul A. Townsend
Author: Anastasis Stephanou

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