循环中的一氧化氮合酶3调节再灌注心肌梗死后的左心室重构。
Circulating NOS3 modulates left ventricular remodeling following reperfused myocardial infarction.
作者信息
Gorressen Simone, Stern Manuel, van de Sandt Annette M, Cortese-Krott Miriam M, Ohlig Jan, Rassaf Tienush, Gödecke Axel, Fischer Jens W, Heusch Gerd, Merx Marc W, Kelm Malte
机构信息
Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Medical Faculty, Department of Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Düsseldorf, Germany.
出版信息
PLoS One. 2015 Apr 14;10(4):e0120961. doi: 10.1371/journal.pone.0120961. eCollection 2015.
PURPOSE
Nitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.
METHODS
To analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.
RESULTS
Three weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5) were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001) and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01) compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16). Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001) compared to BC+/EC+ (15.9±0.5; n = 16), and increased collagen type I and III subtypes.
CONCLUSION
Circulating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.
目的
一氧化氮（NO）由一氧化氮合酶（NOS3）的同工型3组成性地产生并从内皮和几种血细胞类型中释放。我们已经表明，NO可预防心肌缺血/再灌注（I/R）损伤，并且在缺血/再灌注24小时内，缺乏循环NOS3的嵌合小鼠中循环NOS3的耗竭会增加心肌梗死（MI）的面积。在当前研究中，我们假设循环NOS3也会影响再灌注心肌梗死后左心室的重塑。
方法
为了分析循环NOS3的作用，我们将NOS3基因敲除小鼠和野生型（WT）小鼠的骨髓移植到WT小鼠中，产生仅在血管内皮中表达NOS3（BC-/EC+）或在血细胞和血管内皮中均表达NOS3（BC+/EC+）的嵌合体。两组在再灌注心肌梗死的闭胸模型中进行60分钟的冠状动脉闭塞。在心肌梗死后的3周内，通过超声心动图连续评估左心室的结构和功能重塑（24小时、4天、1周、2周和3周）。在心肌梗死后72小时，通过定量逆转录-聚合酶链反应（RT-PCR）分析确定几种细胞外基质（ECM）修饰分子的基因表达。在心肌梗死后3周，通过压力导管获得血流动力学数据，通过Gomori一步三色染色法在死后定量瘢痕大小和胶原含量。
结果
心肌梗死后3周，与BC+/EC+组相比（收缩末期容积：35.6±2.2μl；舒张末期容积：69.1±2.6μl；左心室舒张末压：83.2±3.2mmHg；瘢痕大小/左心室：13.8±0.7%），BC-/EC+组的左心室收缩末期容积（53.2±5.9μl；***p≤0.001；n = 5）和舒张末期容积（82.7±5.6μl；*p<0.05；n = 5）显著增加，同时左心室舒张末压降低（67.5±1.8mmHg；n = 18；***p≤0.001），瘢痕大小/左心室增加（19.5±1.5%；n = 13；**p≤0.01）。与BC+/EC+组（15.9±0.5；n = 16）相比，BC-/EC+组的心肌瘢痕总胶原含量增加（20.2±0.8%；n = 13；***p≤0.001），I型和III型胶原亚型增加。
结论
循环NOS3可改善再灌注心肌梗死后左心室的适应性不良重塑。
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