Cardioadaptation induced by cyclic ischemic preconditioning is mediated by translational regulation of de novo protein synthesis.

Repetitive episodes of brief ischemia induce myocardial adaptation to prolonged ischemia. To investigate whether this myocardial adaptive response involves gene transcription and de novo protein synthesis, this study examined the effects of actinomycin D (ActD) and cycloheximide (Chx) on the cardioprotection induced by repeated ischemic preconditioning. Isolated, perfused working rat hearts underwent cyclic ischemia (CI, four 5-min ischemic intervals, 37 degrees C) with and without pretreatment with Chx (1.0 mg/kg, ip; translation inhibition) or ActD (1.5 mg/kg, ip; transcription inhibition) 3 hr prior to heart isolation. All hearts were subjected to 20 min global ischemia (37 degrees C) and 40 min reperfusion (I/R). Coronary effluent was assayed for creatine kinase (CK) activity. Myocardial tissue was homogenized and crude protein content determined. CI preconditioning improved postischemic recovery of cardiac output (CO; 48 +/- 5.1% vs 73 +/- 2.8% for control and CI, respectively, P < 0.05) and reduced CK release (61 +/- 8.5 U/L vs 38 +/- 4.2 U/L for control and CI, respectively, P < 0.05). The beneficial effects of CI preconditioning on myocardial function and cellular integrity were abolished by Chx while ActD had no effect. Myocardial protein content was increased in CI preconditioned myocardium relative to control hearts (5082 +/- 89 microg/g vs. 4459 +/- 260 microg/g, respectively, P < 0.05). Similarly, pretreatment with Chx but not ActD prevented the increase in myocardial protein content (Chx + CI, 4020 +/- 254 microg/g; ActD + CI, 5049 +/- 68 microg/g, P < 0.05 Chx + CI vs CI or ActD + CI). Myocardial dry/wet weight ratios were not different between groups (P > 0.05). We conclude that CI preconditioning induces protein synthesis-dependent myocardial protection against I/R injuries. CI-induced de novo protein synthesis in the myocardium appears to be regulated at the translational level rather than by gene transcription.