Preconditioning in rat hearts is independent of mitochondrial F₁F₀ATPase inhibition

Abstract

Mitochondrial F1F0adenosinetriphosphatase (ATPase) is responsible for the majority of ATP synthesis during normoxic conditions, but under ischemic conditions it accounts for significant ATP hydrolysis. A previous study showed that preconditioning in isolated rat hearts is mediated by inhibition of this ATPase during ischemia. We tested this hypothesis in our isolated rat heart model of preconditioning. Preconditioning was accomplished by three 5-min periods of global ischemia separated by 5 min of reperfusion. This was followed by 20 min of global ischemia and 30 min of reperfusion. Preconditioning significantly enhanced reperfusion contractile function and reduced lactate dehydrogenase release but paradoxically reduced the time to onset of contracture during global ischemia. Myocardial ATP was depleted at a faster rate during the prolonged ischemia in preconditioned than in sham-treated hearts, which is consistent with the reduced time to contracture. ATP during reperfusion was repleted more rapidly in preconditioned hearts, which is consistent with their enhanced contractile function. Preconditioning significantly reduced lactate accumulation during the prolonged ischemia. We were not able to demonstrate that mitochondrial F1F0ATPase (measured in submitochondrial particles) was inhibited by preconditioning before or during the prolonged ischemia. The mitochondrial ATPase inhibitor oligomycin significantly conserved ATP during ischemia and increased the time to the onset of contracture, which is consistent with inhibition of the mitochondrial ATPase. Our results show that preconditioning in rat hearts can be independent of mitochondrial ATPase inhibition as well as ATP conservation.

Local delivery of PKCε-activating peptide mimics ischemic preconditioning in aged hearts through GSK-3β but not F1-ATPase inactivation

“…Alternatively, agerelated reductions may hinder ATP synthesis on reperfusion and exacerbate ischemic intolerance (35,36). Although some studies have shown no role for F 1 -ATPase in IPC protection (10,21), others have found that IPC leads to F 1 -ATPase inhibition in early ischemia (2,24). Recently, Akt-dependent phosphorylation of F 1 -ATPase has also been demonstrated and localized to the ␤-subunit, which also binds 14-3-3 proteins in plants and ATPase inhibitor protein IF-1 (8,14,42).…”

Pharmacological Profile of the Selective Mitochondrial F1F0 ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

“…It should be pointed out that two separate groups could not show any effect of preconditioning on hydrolase activity and could not link this mechanism to that of preconditioning [51,52], so this issue is not completely resolved at this time. It should be pointed out that preconditioning reduces the time to contracture in our hands [52] and the profile for preconditioning appears different from the profile of BMS-199264.…”

Preconditioning Results in S -Nitrosylation of Proteins Involved in Regulation of Mitochondrial Energetics and Calcium Transport

“…However, when the rate of the F1-ATPase was measured in submitochondrial particles, no differences in activity were observed between IPC and non-IPC hearts. 30,31 Because S-nitrosylation is easily reversed, particularly if the samples are exposed to light and metal ions, 32 it is likely that the IPC mediated S-nitrosylation of the F1-ATPase would be lost during isolation of the submitochondrial particles in those studies.…”