Pharmacological elevation of circulating bioactive phosphosphingolipids enhances myocardial recovery after acute infarction

Yuri M. Klyachkin, Prabakara R. Nagareddy, Shaojing Ye, Marcin Wysoczynski, Ahmed Asfour, Erhe Gao, Manjula Sunkara, Ja A. Brandon, Rahul Annabathula, Rakesh Ponnapureddy, Matesh Solanki, Zahida H. Pervaiz, Susan S. Smyth, Mariusz Z. Ratajczak, Andrew J. Morris, Ahmed Abdel-Latif

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Acute myocardial infarction (AMI) triggers mobilization of bone marrow (BM)-derived stem/progenitor cells (BMSPCs) through poorly understood processes. Recently, we postulated a major role for bioactive lipids such as sphingosine-1 phosphate (S1P) in mobilization of BMSPCs into the peripheral blood (PB). We hypothesized that elevating S1P levels after AMI could augment BMSPC mobilization and enhance cardiac recovery after AMI. After AMI, elevating bioactive lipid levels was achieved by treating mice with the S1P lyase inhibitor tetrahydroxybutylimidazole (THI) for 3 days (starting at day 4 after AMI) to differentiate between stem cell mobilization and the known effects of S1P on myocardial ischemic pre- and postconditioning. Cardiac function was assessed using echocardiography, and myocardial scar size evolution was examined using cardiac magnetic resonance imaging. PB S1P and BMSPCs peaked at 5 days after AMI and returned to baseline levels within 10 days (p < .05 for 5 days vs. baseline). Elevated S1P paralleled a significant increase in circulating BMSPCs (p < .05 vs. controls). We observed a greater than twofold increase in plasma S1P and circulating BMSPCs after THI treatment. Mechanistically, enhanced BMSPC mobilization was associated with significant increases in angiogenesis, BM cell homing, cardiomyocytes, and c-Kit cell proliferation in THI-treated mice. Mice treated with THI demonstrated better recovery of cardiac functional parameters and a reduction in scar size. Pharmacological elevation of plasma bioactive lipids after AMI could contribute to BMSPC mobilization and could represent an attractive strategy for enhancing myocardial recovery and improving BMSC targeting.

Original languageEnglish
Pages (from-to)1333-1343
Number of pages11
JournalStem cells translational medicine
Volume4
Issue number11
DOIs
StatePublished - Nov 2015

Bibliographical note

Publisher Copyright:
© AlphaMed Press 2015.

Keywords

  • Ceramide-1 phosphate
  • Mobilization
  • Myocardial infarction
  • Regeneration
  • Sphingosine-1 phosphate
  • Sphingosine-1 phosphate lyase
  • Stem cells
  • Tetrahydroxybutylimidazole

ASJC Scopus subject areas

  • General Medicine

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