Inhibition of Glycogen Synthase Kinase-3β Improves Tolerance to Ischemia in Hypertrophied Hearts Rodrigo Barillas, MD, MBA, Ingeborg Friehs, MD, Hung.

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Inhibition of Glycogen Synthase Kinase-3β Improves Tolerance to Ischemia in Hypertrophied Hearts Rodrigo Barillas, MD, MBA, Ingeborg Friehs, MD, Hung Cao-Danh, PhD, Joseph F. Martinez, DVM, Pedro J. del Nido, MD The Annals of Thoracic Surgery Volume 84, Issue 1, Pages 126-133 (July 2007) DOI: 10.1016/j.athoracsur.2007.02.015 Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 End-diastolic pressure measured before ischemia and 30 minutes after reperfusion (expressed in mm Hg) with and without inhibitors (lithium [Li] or indirubin-3′-monoxime,5-iodo- [IMI]) as cardioplegic additives. *p < 0.001 versus preischemia; #p < 0.001 versus hypertrophy (Hyp). (H+Li = hypertrophy plus Li; H+IMI = hypertrophy plus IMI.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Developed pressure before (black bars) and after (white bars) ischemia in untreated hypertrophied hearts and treated hypertrophied hearts. *p < 0.001 versus hypertrophy before ischemia; #p < 0.001 versus hypertrophy after ischemia. (H+Li = hypertrophy plus Li; H+IMI = hypertrophy plus IMI; IMI = indirubin-3′-monoxime,5-iodo-; Li = lithium.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 A representative Western immunoblot of glycogen synthase kinase-3β (GSK-3β) expression in normal control hearts and hypertrophied hearts. There was no significant difference in protein levels in hypertrophied versus normal age-matched control hearts. (Hyp = hypertrophy.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 In vitro measurement of glycogen synthase kinase-3 (GSK-3) activity. The GSK-3 activity (expressed as counts per minute [CPM] of protein content) was determined using the experimental concentrations of both inhibitors (0.1 mM lithium [Li], and 1 μM indirubin-3′-monoxime,5-iodo-[IMI]) in untreated hypertrophied perfused hearts. *p < 0.001 versus untreated hypertrophy. (Hyp+Li = untreated hypertrophy plus Li; Hyp+IMI = untreated hypertrophy plus IMI.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 In vivo measurements of glycogen synthase kinase-3 (GSK-3) activity. The GSK-3 activity (expressed as counts per minute [CPM] of protein content) was measured in tissue collected at end-ischemia in untreated and treated hypertrophied hearts. *p < 0.001 versus hypertrophy. (H+Li = hypertrophy plus Li; H+IMI = hypertrophy plus IMI; IMI = indirubin-3′-monoxime,5-iodo-; Li = lithium.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 6 Lactate production (coronary effluent during first 2 minutes of reperfusion) during ischemia in hypertrophied hearts receiving cardioplegic solution with and without lithium (Li) or indirubin-3′-monoxime, 5-iodo- (IMI). *p < 0.001 versus hypertrophy. (H+Li = hypertrophy plus Li; H+IMI = hypertrophy plus IMI.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions

Fig 7 (A) A representative immunoblot indicates that there is no difference in Akt-1 expression levels between hypertrophied hearts and age-matched control hearts. (B) The Akt-1 activity indicated by detection of degree of phosphorylation of a substrate. Glycogen synthase kinase-3 (GSK-3) fusion protein was used as substrate. The phosphorylated product is detected by immunblotting at a molecular weight of 32 kDa. (C) The summary of densitometry data indicates that Akt-1 activity is decreased in hypertrophied hearts during ischemia. *p < 0.05 versus hypertrophy. (Black bar = control; white bar = hypertrophy.) The Annals of Thoracic Surgery 2007 84, 126-133DOI: (10.1016/j.athoracsur.2007.02.015) Copyright © 2007 The Society of Thoracic Surgeons Terms and Conditions