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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/H1193    most recent 01032.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Yeh, C.-C. Articles by Mann, M. J. Search for Related Content PubMed PubMed Citation Articles by Yeh, C.-C. Articles by Mann, M. J.

Sphingolipid signaling and treatment during remodeling of the uninfarcted ventricular wall after myocardial infarction

¹Division of Cardiothoracic Surgery, University of California and Department of Veterans Affairs Medical Center, ²Department of Microbiology-Immunology, University of California, ³Division of Cardiology, University of California and Department of Veterans Affairs Medical Center, and ⁴Liver Study Unit, Department of Veterans Affairs Medical Center, San Francisco, California

Submitted 22 September 2008 ; accepted in final form 18 February 2009

The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway, known to determine the fate and growth of various cell types, can enhance cardiac myocyte survival in vitro and provide cardioprotection in acute ex vivo heart preparations. However, the relevance of these findings to chronic cardiac pathology has never been demonstrated. We hypothesized that S1P signaling is impaired during chronic remodeling of the uninfarcted ventricle during the evolution of post-myocardial infarction (MI) cardiomyopathy and that a therapeutic enhancement of S1P signaling would ameliorate ventricular dysfunction. SphK expression and activity were measured in the remote, uninfarcted myocardium (RM) of C57Bl/6 mice subjected to coronary artery ligation. The mRNA expression of S1P receptor isoforms was also measured, as was the activation of the downstream S1P receptor mediators. A cardioprotective role for S1P₁ receptor agonism was tested via the administration of the S1P₁-selective agonist SEW2871 during and after MI. As a result, the expression data suggested that a dramatic reduction in SphK activity in the RM early after MI may reflect a combination of posttranscriptional and posttranslational modulation. SphK activity continued to decline gradually during chronic post-MI remodeling, when S1P₁ receptor mRNA also fell below baseline. The S1P₁-specific agonism with oral SEW2871 during the first 2-wk after MI reduced apoptosis in the RM and resulted in improved myocardial function, as reflected in the echocardiographic measurement of fractional shortening. In conclusion, these results provide the first documentation of alterations in S1P-mediated signaling during the in situ development of cardiomyopathy and suggest a possible therapeutic role for the pharmacological S1P receptor agonism in the post-MI heart.

sphingosine 1-phosphate; apoptosis