Preconditioning protects the severely atherosclerotic mouse heart

Background. Coronary atherosclerosis has profound effects on vascular and myocardial biology, and it has been speculated that the atherosclerotic heart does not benefit from ischemic preconditioning. Methods. To investigate if atherosclerosis would influence the preconditioning response, Apolipoprotein E/low density lipoprotein (LDL) receptor double knockout mice (ApoE/LDLr−/−) were fed an atherogenic diet (21% fat, 0.15% cholesterol) for 6 to 8 months. At that time, extensive atherosclerotic lesions throughout the coronary tree were seen in transverse sections stained with Oil Red-O. Hearts of ApoE/LDLr−/− mice were Langendorff-perfused with 40 minutes of global ischemia and 60 minutes reperfusion, and compared with C57BL/6 controls. Preconditioning with two episodes of 2 minutes of ischemia and 5 minutes reperfusion, or exposing the mice to a hyperoxic environment (O2 > 98%) for 60 minutes before heart perfusion, was performed. Results. Hearts of mice with coronary atherosclerosis had worse postischemic function, and increased infarct size and troponin T release compared to hearts of C57BL/6 mice. Ischemic preconditioning improved postischemic ventricular function, and reduced myocardial infarct size and troponin T release in both normal and ApoE/LDLr−/− mice. The effects were most pronounced in ApoE/LDLr−/− hearts. Exposure to hyperoxia exerted a similar protection of function and cell viability of ApoE/LDLr−/− mice hearts. Conclusions. These findings suggest that the severely atherosclerotic heart may be protected by preconditioning induced by ischemia or hyperoxia.