HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 43, 31366-31372, October 26, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/43/31366    most recent M705268200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dzeja, P. P. Articles by Terzic, A. Search for Related Content PubMed PubMed Citation Articles by Dzeja, P. P. Articles by Terzic, A. Social Bookmarking                      What's this?

Defective Metabolic Signaling in Adenylate Kinase AK1 Gene Knock-out Hearts Compromises Post-ischemic Coronary Reflow^*

Petras P. Dzeja¹, Peter Bast, Darko Pucar, Be Wieringa, and Andre Terzic²

From the Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, Minnesota 55905 and the Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands

Matching blood flow to myocardial energy demand is vital for heart performance and recovery following ischemia. The molecular mechanisms responsible for transduction of myocardial energetic signals into reactive vasodilatation are, however, elusive. Adenylate kinase, associated with AMP signaling, is a sensitive reporter of the cellular energy state, yet the contribution of this phosphotransfer system in coupling myocardial metabolism with coronary flow has not been explored. Here, knock out of the major adenylate kinase isoform, AK1, disrupted the synchrony between inorganic phosphate P_i turnover at ATP-consuming sites and -ATP exchange at ATP synthesis sites, as revealed by ¹⁸O-assisted ³¹P NMR. This reduced energetic signal communication in the post-ischemic heart. AK1 gene deletion blunted vascular adenylate kinase phosphotransfer, compromised the contractility-coronary flow relationship, and precipitated inadequate coronary reflow following ischemia-reperfusion. Deficit in adenylate kinase activity abrogated AMP signal generation and reduced the vascular adenylate kinase/creatine kinase activity ratio essential for the response of metabolic sensors. The sarcolemma-associated splice variant AK1 facilitated adenosine production, a function lost in the absence of adenylate kinase activity. Adenosine treatment bypassed AK1 deficiency and restored post-ischemic flow to wild-type levels, achieving phenotype rescue. AK1 phosphotransfer thus transduces stress signals into adequate vascular response, providing linkage between cell bioenergetics and coronary flow.

Received for publication, June 27, 2007 , and in revised form, August 10, 2007.

^* This work was supported by grants from the National Institutes of Health, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Netherlands Organization for Scientific Research, Council for Medical Research (NOW-GMW) Program (901-01-095) and the Dutch Cancer Society (KWF) (KUN 98-1808). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Holds the Mayo Clinic Marriott Family Professorship in Cardiovascular Research.

¹ To whom correspondence should be addressed: 200 First St. SW, Mayo Clinic, Rochester, MN 55905. Tel.: 507-284-2747; Fax: 507-266-9936; E-mail: dzeja.petras{at}mayo.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y.-W. Tan, J. A. Hanson, and H. Yang Direct Mg2+ Binding Activates Adenylate Kinase from Escherichia coli J. Biol. Chem., January 30, 2009; 284(5): 3306 - 3313. [Abstract] [Full Text] [PDF]