Ann Thorac Surg 2007;84:133
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Invited commentary
David J. Chambers, PhD
Cardiac Surgical Research, The Rayne Institute (King’s College London), Guy’s and St. Thomas’ NHS Foundation Trust, St. Thomas’ Hospital, London, SE1 7EH United Kingdom
(Email: david.chambers{at}kcl.ac.uk).
The article by Barillas and colleagues [1] is the latest in an elegant series of studies from this group relating to the effects of ischemia-reperfusion on hypertrophied hearts. The study was conducted on neonatal rabbits that were subjected to aortic banding for 6 weeks to achieve early decompensated hypertrophy, which was shown to reduce tolerance to ischemia-reperfusion. This reduced tolerance is associated with impairment in insulin-induced glucose uptake and seems to be linked to defects in insulin signaling pathway (rather than in glucose transport). The authors hypothesize that glucose synthase kinase-3ß (GSK-3ß; a key intermediate in this pathway) has become activated due to a reciprocal reduction in activity of the regulatory Akt-1 resulting in dephosphorylation (and hence activation) of GSK-3ß. The study demonstrates the effect of inhibiting GSK-3ß activity using either lithium, a nonspecific inhibitor, which is believed to act by enhancing the action of insulin by activating glycogen synthase (inhibited by GSK-3ß activity), or a specific GSK-3ß inhibitor, indirubin-3’-monoxime 5-iodo. The inhibitors were administered to the isolated rabbit hearts by addition to a modified "cardioplegic" solution prior to 30 minutes of normothermic global ischemia and 30 minutes reperfusion.
Interestingly, both inhibitors significantly reduced GSK-3ß activity and this was associated with significant improvement in ventricular function (ie, reduced stiffness and improved developed pressure) when compared with untreated hypertrophied hearts, and comparable with age-matched nonhypertrophic hearts. Levels of Akt-1 were shown to be higher in nonhypertrophied control hearts compared with hypertrophied hearts; however, Akt-1 levels were not measured in the treated hearts, and so the hypothesis that there is a reciprocal activation and inhibition between GSK-3ß and Akt-1 was not confirmed. This is unfortunate as it would have provided a convincing rationale for the thesis proposed in this study, and may be worth investigating in future studies. The authors suggest that the improved function in the treated hearts results from increased anaerobic glycolysis generating more glycolytically-derived ATP (shown to be beneficial to ischemic-reperfused myocardium). However, the cardioplegia used in this study (although not defined) appears to contain a high exogenous glucose concentration (
10 mmol/L) together with insulin (10 U/L); the authors speculate that the inhibition of GSK-3ß may lead to enhanced endogenous glucose uptake and increase anaerobic glycolysis, although this will only occur briefly during the initial few minutes of ischemia, and the increased lactate release during early reperfusion seems to confirm this possibility. Whether this would increase adenosine triphosphate levels sufficiently to prevent the observed dysfunction remains to be determined. Clinically, cardioplegic solutions do not usually contain these high insulin and glucose levels, and so exogenous glucose will be limited; it would have been of interest to use a more clinically relevant cardioplegic solution for drug administration purposes to determine whether similar results are achieved without these additional components. It is also surprising that the authors did not show data (or did not measure) for GSK-3ß, Akt-1, and lactate in control nonhypertrophied hearts, because these might be expected to give similar results to the treated hypertrophied hearts (ie, assuming that the inhibitor effect is to revert the defective signaling mechanism back to relative normality). However, the mechanism is likely to be considerably more complicated than this, but the results described in this very interesting and well-conducted study suggest promising new therapeutic options for both immature hearts with congenital hypertrophic defects and also for adult patients with hypertrophy arising from heart failure.
 |
References
|
|---|
- Barillas R, Friehs I, Cao-Danh H, Martinez JF, del Nido PJ. Inhibition of glycogen synthase kinase-3ß improves tolerance to ischemia in hypertrophied hearts Ann Thorac Surg 2007;84:126-133.[Abstract/Free Full Text]
Related Article
-
Inhibition of Glycogen Synthase Kinase-3ß Improves Tolerance to Ischemia in Hypertrophied Hearts
- Rodrigo Barillas, Ingeborg Friehs, Hung Cao-Danh, Joseph F. Martinez, and Pedro J. del Nido
Ann. Thorac. Surg. 2007 84: 126-133.
[Abstract]
[Full Text]
[PDF]
Top
References