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Cardiovascular Research Advance Access first published online on October 25, 2007
This version [Corrected Proof] published online on November 21, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm050
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cGMP signalling in pre- and post-conditioning: the role of mitochondria

Alexandre D.T. Costa1, Sandrine V. Pierre2, Michael V. Cohen3,4, James M. Downey3 and Keith D. Garlid1,*

1 Department of Biology, Portland State University, PO Box 751, Portland, OR 97201, USA
2 Department of Physiology, Pharmacology, Metabolism and Cardiovascular Diseases, University of Toledo College of Medicine, Toledo, OH 43614, USA
3 Department of Physiology, University of South Alabama College of Medicine, Mobile, AL 36688, USA
4 Department of Medicine, University of South Alabama College of Medicine, Mobile, AL 36688, USA

* Corresponding author. Tel: +1 503 725 8967; fax: +1 503 725 3888. E-mail address: garlid{at}pdx.edu

Much of cell death from ischaemia/reperfusion in heart and other tissues is generally thought to arise from mitochondrial permeability transition (MPT) in the first minutes of reperfusion. In ischaemic pre-conditioning, agonist binding to Gi protein-coupled receptors prior to ischaemia triggers a signalling cascade that protects the heart from MPT. We believe that the cytosolic component of this trigger pathway terminates in activation of guanylyl cyclase resulting in increased production of cGMP and subsequent activation of protein kinase G (PKG). PKG phosphorylates a protein on the mitochondrial outer membrane (MOM), which then causes the mitochondrial KATP channel (mitoKATP) on the mitochondrial inner membrane to open, leading to increased production of reactive oxygen species (ROS) by the mitochondria. This implies that the protective signal is somehow transmitted from the MOM to its inner membrane. This is accomplished by a series of intermembrane signalling steps that includes protein kinase C (PKC{varepsilon}) activation. The resulting ROS then activate a second PKC pool which, through another signal transduction pathway termed the mediator pathway, causes inhibition of MPT and reduction in cell death.

KEYWORDS Mitochondrial KATP channel; Mitochondrial permeability transition; Protein kinase C; Protein kinase G; Reperfusion injury

Time for primary review: 16 days


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