Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 290, Issue 2, Pages C583-C591Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00145.2005
Keywords
intracellular Ca2+; kappa-opioid receptor; Na+/Ca2+ exchanger; ryanodine receptor; sarco(endo)plasmic reticulum Ca2+-ATPase
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We hypothesized that activation of heat shock protein 70 (HSP70) by preconditioning, which is known to confer delayed cardioprotection, attenuates the impaired handling of Ca2+ at multiple sites. To test the hypothesis, we determined how the ryanodine receptor (RyR), sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA), and Na+/Ca2+ exchanger (NCX) handled Ca2+ in rat ventricular myocytes preconditioned with a kappa-opioid receptor agonist, U50488H ( UP), followed by blockade of HSP70 with a selective antisense oligonucleotide and subsequently subjected to simulated ischemia. We determined the following: 1) the Ca2+ transients induced by electrical stimulation and caffeine, which provide the overall picture of Ca2+ homeostasis; 2) expression of RyR, SERCA, and NCX; and 3) Ca2+ fluxes via NCX by the use of Ca-45(2+) in the rat ventricular myocyte. We found that UP increased the activity of RyR, SERCA, and NCX and the expression of RyR and SERCA. These effects led to increases in the release of Ca2+ from the sarcoplasmic reticulum via RyR and in the removal of Ca2+ from the cytoplasm by reuptake of Ca2+ to the SR via SERCA and by extrusion of Ca2+ out of the cell via NCX. UP also reduced mitochondrial Ca2+ accumulation. All of the effects of UP were either abolished or significantly attenuated by blockade of HSP70 synthesis with a selective antisense oligonucleotide. The results are evidence that activation of HSP70 by preconditioning improves the ischemia-impaired Ca2+ homeostasis at multiple sites in the heart, which may be responsible, at least partly, for attenuated Ca2+ overload, improved recovery in contractile function, and cardioprotection.
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