F₀F₁ATP synthase activity is differently modulated by coronary reactive hyperemia before and after ischemic preconditioning in the goat

Abstract

Mavelli. F0F1 ATP synthase activity is differently modulated by coronary reactive hyperemia before and after ischemic preconditioning in the goat. Am J Physiol Heart Circ Physiol 287: H2192-H2200, 2004. First published June 24, 2004; doi:10.1152/ajpheart.00327. 2004.-The amplitude of coronary reactive hyperemia (CRH), elicited by 15 s of ischemia, is reduced in hearts subjected to 5 min of ischemic preconditioning (IP). F 0F1 ATP synthase activity and ATP concentration are also altered by IP. We hypothesized that F 0F1 ATP synthase is differently modulated by the inhibitor protein IF 1 during CRH elicited before (CRH np) and after (CRHprec) IP. Hemodynamic parameters were recorded in 10 anesthetized goats. Myocardial biopsies were obtained before IP (C np), during CRHnp, 4 and 6 min after the onset of CRH np, after IP (Cprec), during CRHprec, and 4 min after CRH prec. F0F1 ATP synthase activity, ATP concentration, and ATPto-ADP ratio (ATP/ADP) were determined. Compared with CRH np, IP blunted CRH prec. F0F1 ATP synthase activity transiently increased during CRH np, decreased 4 min after CRHnp, and returned to control 2 min later; it was lower after IP (C prec) and did not change during and after CRH prec. All these changes in activity were modulated by IF1. During CRH np, ATP concentration and ATP/ADP were reduced compared with C np and began to rise 6 min thereafter. During Cprec, both parameters were transiently reduced but increased during and after CRH prec. Hence, during CRHnp, F0F1 ATP synthase activity transiently increases and then decreases significantly. The shortlasting inhibition of the enzyme may explain why a few seconds of occlusion do not induce IP. After IP, F 0F1 ATP synthase activity is blunted, and it is not affected by a subsequent 15 s of occlusion, which induces a blunted CRH prec. These results suggest that postischemic long-lasting inhibition of F 0F1 ATP synthase activity may be a feature of the preconditioned heart. The increase in ATP concentration after preconditioning is in agreement with previous reports of reduced ATP hydrolysis by cytoplasmic ATPases. coronary circulation; energy metabolism; ischemia; mitochondria THE IMMEDIATE SOURCE OF ENERGY for myocardial contraction is provided by the hydrolysis of ATP. Although ATP hydrolysis is carried out by a number of ATPases, its resynthesis is mainly mediated by mitochondrial F 0 F 1 ATP synthase, which couples the transport of protons across the mitochondrial inner membrane to the synthesis of ATP (6,7,12). However, when the proton electrochemical gradient across the inner membrane collapses, the enzyme switches its catalytic activity from ATP synthesis to ATP hydrolysis (12). Although the hydrolytic activity during ischemia counteracts the ischemia-induced collapse of the proton electrochemical gradient across the inner membrane, F 0 F 1 ATP synthase is a major consumer of ATP under ischemic conditions (12, 37). The modulation of F 0 F 1 ATP synthase hydrolytic activity during ischemia may therefore play an important role in mainta...

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

“…Among others, mitochondrial F 1 F 0 ATPase-a-subunit and a-ketoglutaratedehydrogenase were S-nitrosylated, and their activities were inhibited and enhanced, respectively. As said above, these results are in agreement with early studies, indicating that PreC saves post-ischemic ATP consumption, and protects against the loss of a-ketoglutarate activity (145,201).…”

“…Studies suggested at least five phosphorylation sites on the b subunit of the F 1 F 0 ATPase (94). Inhibition of F 1 F 0 ATPase activity may be a feature of the preconditioned heart, thus reducing ATP consumption by reverse mode of the enzyme (145). In the MIM of subsarcolemmal mitochondria, the phosphorylated portion of connexin-43, which plays an important role in ROS formation, increases with ischemia and decreases with PostC (16,146).…”

Serum IF1 concentration is independently associated to HDL levels and to coronary heart disease: the GENES study

“…Also, under acute cholestasis induced by short-term bile duct ligation in rat, the level of IF1 was found increased at the liver plasma membrane, indicating that the IF1-traffi cking pathway might be regulated by hepatobiliary cholesterol metabolism ( 30 ). Moreover, mobilization of mitochondrial IF1 in cardiomyocytes in response to experimental ischemia has been previously reported ( 31,32 ); hence, serum IF1 concentration might partly refl ect a subtle balance between its utilization and release, depending on the cell energetic status. Finally, environmental factors, which are known to modulate HDL levels, had little or no infl uence on IF1 concentrations, suggesting that individual factors (genetic and metabolic) might control serum IF1 levels.…”

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“…In fact, as said, the pore opening depends on calcium levels. 138,192 (Fig 3). The inhibition of F 0 F 1 -ATPase preserves ATP levels and reduces the mitochondrial membrane potential, thereby reducing the driving force for calcium uptake into the mitochondrial matrix, thus increasing tolerance to ischemia 160 .…”