TY - JOUR
T1 - High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury
AU - Moens, An L.
AU - Champion, Hunter C.
AU - Claeys, Marc J.
AU - Tavazzi, Barbara
AU - Kaminski, Pawel M.
AU - Wolin, Michael S.
AU - Borgonjon, Dirk J.
AU - Van Nassauw, Luc
AU - Haile, Azeb
AU - Zviman, Muz
AU - Bedja, Djahida
AU - Wuyts, Floris L.
AU - Elsaesser, Rebecca S.
AU - Cos, Paul
AU - Gabrielson, Kathy L.
AU - Lazzarino, Giuseppe
AU - Paolocci, Nazareno
AU - Timmermans, Jean Pierre
AU - Vrints, Christiaan J.
AU - Kass, David A.
N1 - Copyright the Publisher 2008. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2008/4
Y1 - 2008/4
N2 - BACKGROUND - The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury. METHODS AND RESULTS - Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5×10 mol/L IC) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (ΔdP/dtmax, -878±586 versus -1956±351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3±5.3% versus 5.1±0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (-78.4±9.3% versus -71.2±13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740±58 nmol/g; ischemia, 947±55 nmol/g; ischemia plus FA, 1332±101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124±280 cpm/mg FA versus 5898±474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8±1.2% versus 60.3±4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA. CONCLUSIONS - FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.
AB - BACKGROUND - The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury. METHODS AND RESULTS - Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5×10 mol/L IC) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (ΔdP/dtmax, -878±586 versus -1956±351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3±5.3% versus 5.1±0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (-78.4±9.3% versus -71.2±13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740±58 nmol/g; ischemia, 947±55 nmol/g; ischemia plus FA, 1332±101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124±280 cpm/mg FA versus 5898±474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8±1.2% versus 60.3±4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA. CONCLUSIONS - FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.
UR - http://www.scopus.com/inward/record.url?scp=41949135887&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.107.725481
DO - 10.1161/CIRCULATIONAHA.107.725481
M3 - Article
C2 - 18362233
AN - SCOPUS:41949135887
SN - 0009-7322
VL - 117
SP - 1810
EP - 1819
JO - Circulation
JF - Circulation
IS - 14
ER -