Barandon Laurent, Couffinhal Thierry, Dufourcq Pascale, Ezan Jérome, Costet Pierre, Daret Danièle, Deville Claude, Duplàa Cécile
Pr Deville Department of Cardio-Vascular Surgery, Haut-Lévêque Hospital, Pessac 33604, France.
Eur J Cardiothorac Surg. 2004 Jan;25(1):76-83. doi: 10.1016/s1010-7940(03)00506-2.
Frizzled A is a very recent protein expressed in the cardiovascular hood by cardiomyocytes and by endothelial cells. This protein plays key roles in vitro in vascular cell proliferation and is able to induce an in vivo angiogenic response. Regarding these properties, we assess the hypothesis that Frizzled A could act in the healing process after myocardial infarction.
To investigate the role of Frizzled A, we established a transgenic mouse line overexpressing the protein and developed a model of myocardial infarction by coronary artery ligation.
The incidence of cardiac rupture after myocardial infarction was reduced in transgenic mice (6.5 versus 26.4% in controls, n=165; P<0.01). Infarct sizes were smaller in transgenic mice (18% of left ventricle circumference versus 28.1% in control at day 30; P<0.001; n=6) and the cardiac function was improved (3800 +/- 370 versus 2800 +/- 840 mmHg/s dp/dtmax in controls, -2800 +/- 440 versus -1800 +/- 211 dp/dtmin in controls at day 15; P<0.001; n=6). Early leukocyte infiltration had decreased in transgenic mice during the first week (103 +/- 59 versus 730 +/- 463 cells/mm2 in controls at day 7; P<0.001; n=6) and the apoptotic index was decreased by 50% at day 7. Capillary density in the scar was higher in transgenic mice (290 +/- 103 versus 104 +/- 43 vessels/mm2 in control at day 15; P<0.001) and vessels were more muscularized and mean lumen area was 3-fold higher (952 +/- 902 versus 313 +/- 350 microm2 in control; P<0.001).
Overexpression of Frizzled A reduced the infarct size, improved cardiac recovery, modified inflammatory response and amplified angiogenesis. For these reasons, this protein would be of interest for cardiac surgeons using angiogenic therapy (as gene or protein injection) in ischemic heart diseases in non-revascularizable patients.
卷曲蛋白A是一种最近发现的由心肌细胞和内皮细胞在心血管区域表达的蛋白质。该蛋白在体外对血管细胞增殖起关键作用，并能够诱导体内血管生成反应。基于这些特性，我们评估卷曲蛋白A可能在心肌梗死后的愈合过程中发挥作用的假说。
为了研究卷曲蛋白A的作用，我们建立了过表达该蛋白的转基因小鼠品系，并通过冠状动脉结扎建立了心肌梗死模型。
转基因小鼠心肌梗死后心脏破裂的发生率降低（6.5% 对比对照组的26.4%，n = 165；P < 0.01）。转基因小鼠的梗死面积更小（第30天时左心室周长的18% 对比对照组的28.1%；P < 0.001；n = 6），心脏功能得到改善（第15天时，dp/dtmax为3800 ± 370对比对照组的2800 ± 840 mmHg/s，dp/dtmin为 -2800 ± 440对比对照组的 -1800 ± 211；P < 0.001；n = 6）。在第一周，转基因小鼠的早期白细胞浸润减少（第7天时103 ± 59对比对照组的730 ± 463个细胞/mm²；P < 0.001；n = 6），并且在第7天时凋亡指数降低了50%。转基因小鼠瘢痕中的毛细血管密度更高（第15天时290 ± 103对比对照组的104 ± 43条血管/mm²；P < 0.001）且血管肌化程度更高，平均管腔面积大3倍（952 ± 902对比对照组的313 ± 350 μm²；P < 0.001）。
卷曲蛋白A的过表达减小了梗死面积，改善了心脏恢复，改变了炎症反应并增强了血管生成。基于这些原因，这种蛋白质对于在不可行血管重建术的患者的缺血性心脏病中使用血管生成疗法（如基因或蛋白质注射）的心脏外科医生来说可能具有重要意义。
