High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury
High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury
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DOI：
10.1161/circulationaha.107.725481
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发表时间：
2008-04-08
期刊：
影响因子：
37.8
通讯作者：
Kass, David A.
中科院分区：
文献类型：
--
作者：
Moens, An L.;Champion, Hunter C.;Kass, David A.
背景-维生素B叶酸(FA)对线粒体蛋白质和核酸的合成很重要，是一种抗氧化剂，并能增强一氧化氮合酶的活性。方法和结果：Wistar大鼠接受FA(10 mg/d)或安慰剂1周的预处理，然后进行在体短暂左冠状动脉闭塞30分钟加或不加再灌流90分钟(总计131只，用于各种分析的亚组)。对照组(n=28)采用FA(4.5×10~(-6)m ol/L IC)预处理和全脑缺血/再灌流(30min/30min)。缺血30min后，对照组整体功能下降幅度大于FA组(-878+/-586vs-1956+/-351 mm Hg/S安慰剂；P=0.03)，局部增厚保存较好(37.3±-5.3%vs 5.1+/-0.6%安慰剂；P=0.004)。30分钟时前壁血流灌注率下降(-78.4+/-9.3%比-71.2+/-13.8%安慰剂)，但对照组因缺血而减少的高能磷酸盐ATP和ADP在FA预处理后得到更好的保存(ATP：对照组，2740+/-58nmol/g；缺血，947+/-55nmol/g；缺血+FA，1332+/-101nmol/g；P=0.02)。基础氧尿酸(黄嘌呤、次黄嘌呤和尿酸)在FA预处理后升高，但在缺血期间增加的幅度小于对照组。缺血超氧阴离子产生减少(3124+/-280cpm/mg FA比5898+/-474cpm/mg安慰剂；P=0.001)。再灌注后，FA处理的心脏有较小的梗塞(3.8%+/-1.2%比60.3+/-4.1%的危险区域；P<；0.002)和较少的收缩带坏死，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性，超氧化物和一氧化氮合酶去偶联。心肌梗死面积缩小与1 mg/d FA相似。结论FA可减轻缺血时的心肌功能障碍，改善缺血后损伤。这与高能磷酸盐的保存、减少随后的活性氧生成、eNOS解偶联和再灌流后细胞死亡有关。
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 x 10(-6) 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 ( Delta dP/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.