Ischemia reperfusion injury, KATP channels, and exercise-induced cardioprotection against apoptosis

Quindry JC, Miller L, McGinnis G, Kliszczewicz B, Irwin JM, Landram M, Urbiztondo Z, Nanayakkara G, Amin R. Ischemia reperfusion injury, K-ATP channels, and exercise-induced cardioprotection against apoptosis. J Appl Physiol 113: 498-506, 2012. First published May 31, 2012; doi:10.1152/japplphysiol.00957.2011.-Exercise is a potent stimulus against cardiac ischemia reperfusion (IR) injury, although the protective mechanisms are not completely understood. The study purpose was to examine whether the mitochondrial or sarcolemmal ATP-sensitive potassium channel (mito K-ATP or sarc K-ATP, respectively) mediates exercise-induced cardioprotection against post-IR cell death and apoptosis. Eighty-six, 4-mo-old male Sprague Dawley rats were randomly assigned to treadmill exercise (Ex; 30 m/min, 3 days, 60 min, similar to 70 maximal oxygen uptake) and sedentary (Sed) treatments. Rats were exposed to regional cardiac ischemia (50 min) and reperfusion (120 min) or Sham (170 min; no ligation) surgeries. Exercise subgroups received placebo (saline), 5-hydroxydecanoate (5HD; 10 mg/kg ip), or HMR1098 (10 mg/kg ip) to inhibit mito K-ATP or sarc K-ATP channel. Comprehensive outcome assessments included post-IR ECG arrhythmias, cardiac tissue necrosis, redox perturbations, and autophagy biomarkers. No arrhythmia differences existed between exercised and sedentary hearts following extended-duration IR (P < 0.05). The sarc K-ATP channel was confirmed essential (P = 0.002) for prevention of antinecrotic tissue death with exercise (percent infarct, Sed = 42%; Ex = 20%; Ex5HD = 16%; ExHMR = 42%), although neither the mito K-ATP (P = 0.177) nor sarc K-ATP (P = 0.274) channel provided post-IR protection against apoptosis (terminal deoxynucleotidyl transferase deoxy UTP-mediated nick-end labeling-positive nuclei/mm(2), Sham = 1.8 +/- 0.5; Sed = 19.4 +/- 6.7; Ex = 7.5 +/- 4.6; Ex5HD = 14.0 +/- 3.9; ExHMR = 11.1 +/- 1.8). Exercise preconditioning also appears to preserve basal autophagy levels, as assessed by Beclin 1 (P <= 0.001), microtubule-associated protein-1 light-chain 3B ratios (P = 0.020), and P62 (P <= 0.001), in the hours immediately following IR. Further research is needed to better understand these findings and corresponding redox changes in exercised hearts.