Mechanism Discovered for Protective Effects of Cardiac Preconditioning

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 7 No. 3 • June 2004

Mechanism Discovered for Protective Effects of Cardiac Preconditioning

Preconditioning is the protective process that occurs when the heart is exposed to brief periods of reduced oxygen (ischemia). After such exposures, there is a brief (hours to a day or so) period during which the heart is resistant to additional exposures to ischemia and, hence, has reduced amounts of damage and cell death (as compared to nonpreconditioned hearts). Understanding how preconditioning works has been a longtime goal of researchers.

A new paper1 reports discovery of a mechanism that is not only of great theoretical interest but also potentially of great practical use, as there are methods available to make use of it. Many pathways have been found that are involved in preconditioning, but the new paper finds that these all converge on glycogen synthase kinase-3beta, an enzyme that is recognized as a central feature in many signaling systems.2 Lithium and other substances that inhibit glycogen synthase kinase-3beta (GSK-3beta) are cardioprotective. Low-dose lithium is one of the constituents of our new formulation for protecting cognitive abilities.

The authors found that one of the effects of reperfusion injury in the heart is a reduction in the reactive oxygen species threshold for induction of the mitochondrial permeability transition; the latter is an important part of mitochondrial death pathways. They found a number of agents that inhibit GSK-3beta and concluded that “… the general mechanism of protection is the convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex to limit MPT [mitochondrial permeability transition] induction.”

There were two classes of these cardio/neuroprotective agents: in one group, there was protection over a prolonged period of time (hours to a day or two), long after there was a significant amount of the substance in the bloodstream (the authors call this “memory”), while the other group provided protection while the substance was in the bloodstream but not afterward (these had no “memory”). All the substances enhanced the mitochondrial permeability transition reactive oxygen species threshold over control by about 35–50%. The memory group included diazoxide, Hoe, the peptide DADLE, and cyclosporine A, as well as bradykinin. The nonmemory group included receptor tyrosine kinase ligands (insulin and IGF-1), GLP-1, and others, as well as lithium.

The memory group of substances caused mitochondrial swelling by inducing free radicals. The authors found that preconditioning provided by the entire mitochondrial-sweller class (including hypoxic preconditioning) is prevented by reactive oxygen species scavengers. The memory effect thus appears to be due to the induction of free radical protective mechanisms, such as heat shock proteins, which is why you don’t get it if excess free radical scavengers are present. Lithium, a nonsweller, is one of the nonmemory preconditioners and does not depend upon the presence or absence of free radical scavengers.

The authors conclude, “Thus, it might be reasonable to consider adding Li+ (or another GSK-3 inhibitor) to GIK [glucose-insulin-potassium] in the treatment of acute ischemic syndromes, myocardial infarction, and stroke.” We note that, in our judgment a small inhibition of GSK-3beta will still provide worthwhile protection.

Lithium and inhibition of glycogen synthase kinase-3beta in cellular oxidative resistance

In another new study,3 researchers have found that, in clones of a particular type of cell (the mouse hippocampal neuronal cell line HT22) that is resistant to oxidative stress caused by glutamate* and hydrogen peroxide, the amount of inactivated glycogen synthase kinase-3 beta (GSK-3beta) is elevated compared to sensitive clones. They found that pharmacological inhibition of GSK-3beta by lithium in the parental neuronal cells (that are sensitive to oxidative stress) resulted in an increased tolerance to glutamate and hydrogen peroxide, “suggesting that GSK-3beta is involved in the control of oxidative stress resistance in these cells.”

*Glutamate excitotoxicity is thought to be part of the processes causing neurotoxic damage in Alzheimer’s and several other neurologic diseases.

The authors note, “These findings are interesting in the [sic] light of the well-established link between cell survival and GSK-3beta. While GSK-3beta activation is involved in apoptotic (programmed cell death) process, its inhibition is part of antiapoptotic signaling pathways like Wnt-signaling, the PI-3 kinase, and the MAP-kinase pathway.” Moreover, inhibition of GSK-3beta protects cortical and hippocampal cell cultures from the Alzheimer’s protein amyloid-beta-induced cell death.

  1. Juhaszova et al. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition core. J Clin Invest 113(11):1535-49 (2004). Murphy. Inhibit GSK-3beta or there’s heartbreak dead ahead. J Clin Invest 113(11):1526-8.
  2. Jope and Bijur. Mood stabilizers, glycogen synthase kinase-3beta, and cell survival. Molec Psychiatry 7:S35-45 (2002).
  3. Schafer et al. Inhibition of glycogen synthase kinase-3beta is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain Res 1005:84-9 (2004).

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