TY - JOUR
T1 - Pharmacological elevation of circulating bioactive phosphosphingolipids enhances myocardial recovery after acute infarction
AU - Klyachkin, Yuri M.
AU - Nagareddy, Prabakara R.
AU - Ye, Shaojing
AU - Wysoczynski, Marcin
AU - Asfour, Ahmed
AU - Gao, Erhe
AU - Sunkara, Manjula
AU - Brandon, Ja A.
AU - Annabathula, Rahul
AU - Ponnapureddy, Rakesh
AU - Solanki, Matesh
AU - Pervaiz, Zahida H.
AU - Smyth, Susan S.
AU - Ratajczak, Mariusz Z.
AU - Morris, Andrew J.
AU - Abdel-Latif, Ahmed
N1 - Publisher Copyright:
© AlphaMed Press 2015.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
KW - Ceramide-1 phosphate
KW - Mobilization
KW - Myocardial infarction
KW - Regeneration
KW - Sphingosine-1 phosphate
KW - Sphingosine-1 phosphate lyase
KW - Stem cells
KW - Tetrahydroxybutylimidazole
UR - http://www.scopus.com/inward/record.url?scp=84945258781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84945258781&partnerID=8YFLogxK
U2 - 10.5966/sctm.2014-0273
DO - 10.5966/sctm.2014-0273
M3 - Article
C2 - 26371341
AN - SCOPUS:84945258781
SN - 2157-6564
VL - 4
SP - 1333
EP - 1343
JO - Stem cells translational medicine
JF - Stem cells translational medicine
IS - 11
ER -