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.
Highlights
The loss of coronary blood flow for an extended period of time leads to ischemic damage and cardiomyocyte death
We wanted to verify that in our system aged rat hearts have a deficient response to ischemic pre- and post-conditioning
Using an ex vivo rat heart model, we have found that ischemic pre- and postconditioning is less effective in 27-month-old rats relative to 3- to 6-month-old rats
Summary
The loss of coronary blood flow for an extended period of time leads to ischemic damage and cardiomyocyte death. Reoxygenation IR injury is a major complication of acute ischemia/infarction, cardiopulmonary bypass, angioplasty and heart transplantation.[3] hearts can be treated (“conditioned”) in such a way that the damage associated with ischemia and subsequent reoxygenation is greatly diminished.[4,5] Ischemic preconditioning consists of one or more cycles of a short-term non-damaging period of ischemia followed by reperfusion initiated prior to the extended index ischemia and subsequent reperfusion This prevents loss of myocardial function and reduces subsequent infarct size.[4,5] This same treatment can be initiated after the index ischemia just prior to full reperfusion with equal effectiveness.[6] This is referred to as postconditioning. A variety of pharmacologic agents can serve as pre- and post-conditioning agents
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