Pharmacological Elevation of Circulating Bioactive Phosphosphingolipids Enhances Myocardial Recovery After Acute Infarction. (14th September 2015)

• Record Type: Journal Article
• Authors: Klyachkin, Yuri M.; Nagareddy, Prabakara R.; Ye, Shaojing; Wysoczynski, Marcin; Asfour, Ahmed; Gao, Erhe; Sunkara, Manjula; Brandon, Ja A.; Annabathula, Rahul; Ponnapureddy, Rakesh; Solanki, Matesh; Pervaiz, Zahida H.; Smyth, Susan S.; Ratajczak, Mariusz Z.; Morris, Andrew J.; Abdel-Latif, Ahmed
• Is Part Of: Stem cells translational medicine. Volume 4:Number 11(2015)
• Page Start: 1333
• Page End: 1343
• Publication Date: 2015-09-14
• Subjects: Sphingosine-1 phosphate -- Ceramide-1 phosphate -- Sphingosine-1 phosphate lyase -- Tetrahydroxybutylimidazole -- Mobilization -- Myocardial infarction -- Regeneration -- Stem cells; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.5966/sctm.2014-0273
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract : The findings have demonstrated that early transient sphingosine-1 phosphate lyase inhibition after acute myocardial infarction (AMI) correlates with increased stem cell mobilization and homing to the infarct border zones. These data indicate that pharmacological elevation of bioactive lipid levels can be beneficial in the early phase after cardiac ischemic injury and provide the first evidence that carefully timed transient pharmacological upregulation of bioactive lipids after AMI could be therapeutic. 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. Significance: 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.