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It has been widely accepted that ischemic preconditioning (IPC) exhibits a promising and reproducible cardioprotective effect against ischemia/reperfusion (I/R) injury. However, the actual trigger that amplifies the molecular signaling and protects I/R heart is still unclear.To separate the factors involved in IPC, we established a dog double-circuit cardiopulmonary bypass (CPB) model, which consists of a systemic circuit and a coronary circuit. Forty-two male adult beagle dogs were randomly allocated into 7 groups: sham, I/R, IPC, hypoxia preconditioning (HPC), accumulated metabolite preconditioning (MPC), oxygenated or deoxygenated erythrocytes preconditioning (OxyEPC and DeoxyEPC). After pretreatment, dogs were subjected to 2 h-cardiac arrest and 2 h-reperfusion.There were no differences in the cardiac function and hemodynamic parameters at baseline among groups. Like IPC, the hypoxia-related pretreatments HPC and DeoxyEPC improved post-arrest left ventricular systolic/diastolic performance and reduced pulmonary vascular resistance. The cardiac oxygen (O2) utilization was also greatly elevated in these hypoxia-related pretreatment groups, as evidenced by increased cardiac O2 consumption (VO2) and O2 extraction index (O2EI) and suppressed lactate level. Besides, we did not observe improvement of these parameters in the MPC and OxyEPC groups. Further study indicated that these hypoxia-related pretreatments were associated with the attenuation of pro-inflammatory cytokines release and the elevation of complex I-supported mitochondrial respiration.With a dog double-circuit CPB model, we demonstrated that hypoxia is the actual trigger to initiate the cardioprotective effect of IPC in vivo, which was related to reduced cardiac inflammation and ameliorated complex-I supported mitochondrial function.