Document Detail


Sphingolipid signaling and treatment during remodeling of the uninfarcted ventricular wall after myocardial infarction.
MedLine Citation:
PMID:  19234089     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 S1P(1) receptor agonism was tested via the administration of the S1P(1)-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 S1P(1) receptor mRNA also fell below baseline. The S1P(1)-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.
Authors:
Che-Chung Yeh; Hongzhe Li; Deepak Malhotra; Mei-Chuan Huang; Bo-Qing Zhu; Edward J Goetzl; Donald A Vessey; Joel S Karliner; Michael J Mann
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-02-20
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  296     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-03-31     Completed Date:  2009-06-10     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1193-9     Citation Subset:  IM    
Affiliation:
Cardiothoracic Surgery, 4150 Clement St., 112D, San Francisco, CA 94121, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Male
Mice
Mice, Inbred C57BL
Myocardial Infarction / metabolism*,  physiopathology*
Myocytes, Cardiac / drug effects,  metabolism
Oxadiazoles / pharmacology
Phosphotransferases (Alcohol Group Acceptor) / metabolism
RNA, Messenger / metabolism
Receptors, Lysosphingolipid / agonists,  metabolism
Signal Transduction / physiology*
Sphingolipids / metabolism*
Thiophenes / pharmacology
Ventricular Remodeling / physiology*
Grant Support
ID/Acronym/Agency:
1K08-HL-079239/HL/NHLBI NIH HHS; 1R01-HL-083118/HL/NHLBI NIH HHS; 5R01-HL-31809/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Oxadiazoles; 0/RNA, Messenger; 0/Receptors, Lysosphingolipid; 0/SEW2871; 0/Sphingolipids; 0/Thiophenes; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase
Comments/Corrections

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