Cardioprotection with postconditioning: loss of efficacy in murine models of type-2 and type-1 diabetes.
Postconditioning (PostC), or relief of myocardial ischemia in a stuttered manner, has been shown to reduce infarct size, due in part to upregulation of survival kinase signaling. Virtually all of these data have, however, been obtained in healthy adult cohorts; the question of whether PostC-induced cardioprotection is maintained in the setting of clinically relevant comorbidities has remained largely unexplored. Accordingly, our aim was to assess the consequences of a major risk factor-diabetes-on the infarct-sparing effect of stuttered reflow. Isolated buffer-perfused hearts were obtained from normoglycemic C57BL/6J mice, BKS.Cg-m+/+Lepr(db)/J (db/db) mice (model of type-2 diabetes), C57BL/6J mice injected with streptozotocin (model of type-1 diabetes), and streptozotocin-injected mice in which normoglycemia was re-established by islet cell transplantation. All hearts underwent 30  min of ischemia and, within each cohort, hearts received either standard (control) reperfusion or three to six 10-s cycles of stuttered reflow. PostC reduced infarct size via upregulation of extracellular signal-regulated kinase 1/2 in normoglycemic mice. In contrast, diabetic hearts were refractory to PostC-induced cardioprotection-an effect that, in the type-1 model, was reversed by restoration of normoglycemia. We provide novel evidence for a profound-but potentially reversible-diabetes-induced defect in the cardioprotective efficacy of PostC.
Przyklenk
Karin
K
Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA. kprzykle@med.wayne.edu
Maynard
Michelle
M
Greiner
Dale L
DL
Whittaker
Peter
P
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology; D057775:Ischemic Postconditioning; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D011897:Random Allocation; D051381:Rats