title: Sphingosine protects aging hearts from ischemia/reperfusion injury: Superiority to sphingosine 1-phosphate and ischemic pre- and post-conditioning.
abstract: Aging hearts are known to have diminished capacity to be protected against reoxygenation ischemia/reperfusion (IR) injury provided by various cardioprotective regimens. In search of a more successful regimen, we have studied the response of aged hearts to preconditioning (PC) and postconditioning (POST) elicited by sphingosine or sphingosine 1-phosphate treatment.An ex vivo rat heart model was used to study the ability of PC and POST to protect old hearts (27 month) against I/R injury generated by 40 minutes (min) of index ischemia followed by 40 min of reperfusion. The response to ischemic PC was reduced in 27 month old hearts relative to 3-6 month (young) hearts as noted by a poor recovery of left ventricular developed pressure (LVDP) upon reperfusion (45% vs. 74% in young hearts) and a large infarct size after 40 min of reperfusion (37% versus 8% in young hearts). PC with sphingosine 1-phosphate (S1P) was also poor in old hearts yielding only 49% recovery of LVDP and a 27% infarct size. In contrast, PC with sphingosine was unaffected by aging; the 78% recovery of LVDP and 8% infarct size were not different from young hearts. Ischemic POST was less affected by aging than ischemic PC, but the old hearts still experienced infarct sizes of 28%. POST of old hearts with S1P was also associated with a substantial infarct size (24%). However, POST of old hearts with sphingosine was superior to the other forms of POST in that it reduced the infarct size to 12%. S1P levels were found to be lower in old hearts which may contribute to the decreased effectiveness of ischemic PC and POST. Further, phospho-Akt levels and distribution were altered in response to cardioprotection in the old hearts. In conclusion, POST was less affected by aging than PC; and sphingosine is a uniquely effective agent for both PC and POST of aging hearts.
authors.affiliation: Liver Study Unit, Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA. donald.vessey@va.gov
authors.forename: Donald A
authors.initials: DA
authors.lastname: Vessey
authors.forename: Michael
authors.initials: M
authors.lastname: Kelley
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000375:Aging; D000818:Animals; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008246:Lysophospholipids / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020127:Recovery of Function; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure
chemical_list: D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine