Ischemia reperfusion injury, KATP channels, and exercise-induced cardioprotection against apoptosis.
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, ∼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.
Cardioprotection Laboratory, Department of Kinesiology, Auburn University, Auburn, Alabama 36830, USA. jcq0001@auburn.edu
John C
JC
Quindry
Lindsey
L
Miller
Graham
G
McGinnis
Brian
B
Kliszczewicz
J Megan
JM
Irwin
Michael
M
Landram
Zea
Z
Urbiztondo
Gayani
G
Nanayakkara
Rajesh
R
Amin
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D001343:Autophagy / Q000502:physiology; D000071186:Beclin-1; D003652:Decanoic Acids / Q000494:pharmacology; D004562:Electrocardiography; D020719:Glucuronides / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000032:analysis
D000889:Anti-Arrhythmia Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D003652:Decanoic Acids; D020719:Glucuronides; C490981:Gtf2h1 protein, mouse; C487003:HMR 1098 glucuronide; D006880:Hydroxy Acids; D054086:KATP Channels; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D013449:Sulfonamides; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; C052853:5-hydroxydecanoic acid