Document Detail


SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury.
MedLine Citation:
PMID:  21821779     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Stromal cell-derived factor-1α (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose-dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R.
Authors:
Chunyan Huang; Hongmei Gu; Wenjun Zhang; Mariuxi C Manukyan; Weinian Shou; Meijing Wang
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2011-08-05
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  301     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-29     Completed Date:  2011-11-22     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1496-505     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Biotransformation / drug effects
Blotting, Western
Caspases / physiology
Chemokine CXCL12 / physiology*
Extracellular Signal-Regulated MAP Kinases / physiology
Heart / physiology*
L-Lactate Dehydrogenase / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Reperfusion Injury / pathology*
Oncogene Protein v-akt / physiology
Receptors, CXCR4 / physiology*
STAT3 Transcription Factor / genetics,  physiology*
Signal Transduction / physiology
Grant Support
ID/Acronym/Agency:
P01 HL085098/HL/NHLBI NIH HHS; P01 HL085098-05/HL/NHLBI NIH HHS; R00-HL-0876077/HL/NHLBI NIH HHS; R01 HL081092/HL/NHLBI NIH HHS; R01 HL081092-05/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Chemokine CXCL12; 0/Cxcl12 protein, mouse; 0/Receptors, CXCR4; 0/STAT3 Transcription Factor; 0/Stat3 protein, mouse; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 2.7.11.1/Oncogene Protein v-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.4.22.-/Caspases
Comments/Corrections

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