title: Pharmacological Elevation of Circulating Bioactive Phosphosphingolipids Enhances Myocardial Recovery After Acute Infarction.
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.
  
  
  CONCLUSIONS
  Acute myocardial infarction (AMI) initiates innate immune and reparatory mechanisms through which bone marrow-derived stem/progenitor cells (BMSPCs) are mobilized toward the ischemic myocardium and contribute to myocardial regeneration. Although it is clear that the magnitude of BMSPC mobilization after AMI correlates with cardiac recovery, the molecular events driving BMSPC mobilization and homing are poorly understood. The present study confirms the role of bioactive lipids in BMSPC mobilization after AMI and proposes a new strategy that improves cardiac recovery. Inhibiting sphingosine-1 phosphate (S1P) lyase (SPL) allows for the augmentation of the plasma levels of S1P and stem cell mobilization. These findings demonstrate that early transient SPL inhibition after MI correlates with increased stem cell mobilization and their homing to the infarct border zones. Augmenting BMSPC mobilization correlated with the formation of new blood vessels and cardiomyocytes and c-Kit cell proliferation. These novel findings on the cellular level were associated with functional cardiac recovery, reduced adverse remodeling, and a decrease in scar size. Taken together, these data indicate that pharmacological elevation of bioactive lipid levels can be beneficial in the early phase after cardiac ischemic injury. These findings provide the first evidence that a carefully timed transient pharmacological upregulation of bioactive lipids after AMI could be therapeutic, because it results in significant cardiac structural and functional improvements.
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Yuri M
authors.initials: YM
authors.lastname: Klyachkin
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Prabakara R
authors.initials: PR
authors.lastname: Nagareddy
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Shaojing
authors.initials: S
authors.lastname: Ye
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Asfour
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Ja A
authors.initials: JA
authors.lastname: Brandon
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Annabathula
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Ponnapureddy
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Matesh
authors.initials: M
authors.lastname: Solanki
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Zahida H
authors.initials: ZH
authors.lastname: Pervaiz
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.affiliation: Stem Cell Biology Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA, and Veterans Affairs Medical Center, Lexington, Kentucky, USA abdel-latif@uky.edu.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdel-Latif
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D007093:Imidazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000097:blood*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology / Q000628:therapy; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008246:Lysophospholipids; D008565:Membrane Proteins; C060506:sphingosine 1-phosphate; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D013110:Sphingosine
keywords: Ceramide-1 phosphate; Mobilization; Myocardial infarction; Regeneration; Sphingosine-1 phosphate; Sphingosine-1 phosphate lyase; Stem cells; Tetrahydroxybutylimidazole