Cardiovascular research
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Cardiovascular research · Nov 2006
Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation.
Both K(ATP) channel opening drugs and ischaemic preconditioning have been suggested to protect the ischaemic heart by acting on K(ATP) channels in the inner mitochondrial membrane, uncoupling the proton gradient and partially dissipating the mitochondrial membrane potential. The aim of these studies was to use low concentrations of FCCP, a mitochondrial protonophore, to bypass the mitochondrial K(ATP) channel and partially uncouple the mitochondria and establish whether this activates protective pathways within the rat heart analogous to K(ATP) channel openers or preconditioning. ⋯ In the isolated rat heart, partial mitochondrial uncoupling with low-dose FCCP significantly improves post-ischaemic functional recovery via a ROS-dependent pathway. This cardioprotection is not mediated via the depletion of cellular ATP or mitochondrial K(ATP) channel activation.
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Cardiovascular research · Oct 2006
Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism.
This study was undertaken to analyze whether nitric oxide (NO) modulates the human potassium channel hKv1.5, which generates the ultrarapid delayed rectifier current (IKur) that determines the height and duration of atrial action potentials. ⋯ NO inhibits the hKv1.5 current by a cGMP-dependent mechanism and by the S-nitrosylation of the hKv1.5 protein, an effect that contributes to shaping the human atrial action potentials.
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Cardiovascular research · Oct 2006
Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.
We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. ⋯ Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.
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Cardiovascular research · Sep 2006
Mitochondrial Ca2+ uptake during simulated ischemia does not affect permeability transition pore opening upon simulated reperfusion.
Reenergization of ischemic cardiomyocytes may be associated with acute necrotic cell death due in part to cytosolic Ca2+ overload and opening of a permeability transition pore (PTP) in mitochondria. It has been suggested that Ca2+ overload during ischemia primes mitochondria for PTP opening during reperfusion. We investigated the ability of mitochondria to uptake Ca2+ during simulated ischemia (SI) and whether this uptake determines PTP opening and cell death upon simulated reperfusion (SR). ⋯ Mitochondrial Ca2+ uptake during SI buffers cytosolic Ca2+ overload but its magnitude appears not to be an important determinant of PTP opening upon subsequent SR.
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Cardiovascular research · Sep 2006
Low dose N, N-dimethylsphingosine is cardioprotective and activates cytosolic sphingosine kinase by a PKCepsilon dependent mechanism.
N, N-Dimethylsphingosine (DMS) is recognized as an inhibitor of sphingosine kinase (SphK), a key enzyme responsible for the formation of sphingosine-1-phosphate (S1P). We previously showed that S1P was cardioprotective and that SphK was critical for myocardial ischemic preconditioning. Although DMS is an endogenous sphingolipid, its effect on cardiac function and cardioprotection at low concentration has not been studied. ⋯ DMS has a biphasic effect on cardioprotection. Higher concentrations (10 microM) are inhibitory, whereas a low concentration (0.3 microM and 1 microM) of DMS protects murine hearts against ischemia/reperfusion injury. DMS activates SphK in the cytosol via a PKCepsilon dependent mechanism. The PKCepsilon-SphK-S1P-Akt pathway is involved in the cardiac protection induced by DMS.