High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury

被引：129

作者：

Moens, An L. ^{[1
,3
]}

Champion, Hunter C. ^{[1
]}

Claeys, Marc J. ^{[3
]}

Tavazzi, Barbara ^{[5
]}

Kaminski, Pawel M. ^{[6
]}

Wolin, Michael S. ^{[6
]}

Borgonjon, Dirk J. ^{[3
]}

Van Nassauw, Luc

Haile, Azeb ^{[1
]}

Zviman, Muz ^{[1
]}

Bedja, Djahida ^{[1
]}

Wuyts, Floris L. ^{[4
]}

Elsaesser, Rebecca S. ^{[2
]}

Cos, Paul ^{[3
]}

Gabrielson, Kathy L. ^{[1
]}

Lazzarino, Giuseppe ^{[5
]}

Paolocci, Nazareno ^{[1
]}

Timmermans, Jean-Pierre

Vrints, Christiaan J. ^{[3
]}

Kass, David A. ^{[1
]}

机构：

[1] Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21205 USA

[2] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA

[3] Univ Antwerp, Dept Cardiol, B-2020 Antwerp, Belgium

[4] Univ Antwerp, Dept Biomed Stat, B-2020 Antwerp, Belgium

[5] Univ Rome, Dept Chem Sci, Rome, Italy

[6] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA

来源：

CIRCULATION | 2008年 / 117卷 / 14期

关键词：

contractility; folic acid; ischemia; infarction; nitric oxide synthase; reperfusion; superoxide;

D O I：

10.1161/CIRCULATIONAHA.107.725481

中图分类号：

R5 [内科学];

学科分类号：

1002 [临床医学]; 100201 [内科学];

摘要：

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.

引用

页码：1810 / 1819

页数：10

共 38 条

[1]

Relationships between nitric oxide-mediated endothelial function, eNOS coupling and blood pressure revealed by eNOS-GTP cyclohydrolase 1 double transgenic mice [J].