Kamphoven J H, Stubenitsky R, Reuser A J, Van Der Ploeg A T, Verdouw P D, Duncker D J
Department of Clinical Genetics, Experimental Cardiology, Thoraxcenter, Erasmus University Rotterdam, Rotterdam, The Netherlands.
Physiol Genomics. 2001 Apr 27;5(4):171-9. doi: 10.1152/physiolgenomics.2001.5.4.171.
Pompe's disease is an autosomal recessive and often fatal condition, caused by mutations in the acid alpha-glucosidase gene, leading to lysosomal glycogen storage in heart and skeletal muscle. We investigated the cardiac phenotype of an acid alpha-glucosidase knockout (KO) mouse model. Left ventricular weight-to-body weight ratios were increased 6.3 +/- 0.8 mg/g in seven KO compared with 3.2 +/- 0.2 mg/g in eight wild-type (WT) mice (P < 0.05). Echocardiography under ketamine-xylazine anesthesia revealed an increased left ventricular (LV) wall thickness (2.17 +/- 0.16 in KO vs. 1.18 +/- 0.10 mm in WT mice, P < 0.05) and a decreased LV lumen diameter (2.50 +/- 0.32 in KO vs. 3.21 +/- 0.14 mm in WT mice, P < 0.05), but LV diameter shortening was not different between KO and WT mice. The maximum rate of rise of left ventricular pressure (LV dP/dt(max)) was lower in KO than in WT mice under basal conditions (2,720 +/- 580 vs. 4,440 +/- 440 mmHg/s) and during dobutamine infusion (6,220 +/- 800 vs. 8,730 +/- 790 mmHg/s, both P < 0.05). Similarly, during isoflurane anesthesia LV dP/dt(max) was lower in KO than in WT mice under basal conditions (5,400 +/- 670 vs. 8,250 +/- 710 mmHg/s) and during norepinephrine infusion (10,010 +/- 1,320 vs. 14,710 +/- 220 mmHg/s, both P < 0.05). In conclusion, the markedly increased LV weight and wall thickness, the encroachment of the LV lumen, and LV dysfunction reflect cardiac abnormalities, although not as overt as in humans, of human infantile Pompe's disease and make these mice a suitable model for further investigation of pathophysiology and of novel therapies of Pompe's disease.
庞贝氏病是一种常染色体隐性且通常致命的疾病，由酸性α-葡萄糖苷酶基因突变引起，导致心脏和骨骼肌中溶酶体糖原蓄积。我们研究了酸性α-葡萄糖苷酶基因敲除（KO）小鼠模型的心脏表型。7只KO小鼠的左心室重量与体重之比为6.3±0.8mg/g，而8只野生型（WT）小鼠为3.2±0.2mg/g（P<0.05）。在氯胺酮-赛拉嗪麻醉下进行超声心动图检查发现，KO小鼠的左心室（LV）壁厚度增加（KO小鼠为2.17±0.16mm，WT小鼠为1.18±0.10mm，P<0.05），LV腔直径减小（KO小鼠为2.50±0.32mm，WT小鼠为3.21±0.14mm，P<0.05），但KO小鼠和WT小鼠之间的LV直径缩短情况无差异。在基础状态下，KO小鼠的左心室压力最大上升速率（LV dP/dt(max)）低于WT小鼠（分别为2,720±580和4,440±440mmHg/s），在多巴酚丁胺输注期间也是如此（分别为6,220±800和8,730±790mmHg/s，均P<0.05）。同样，在异氟烷麻醉下，基础状态下KO小鼠的LV dP/dt(max)低于WT小鼠（分别为5,400±670和8,250±710mmHg/s），在去甲肾上腺素输注期间也是如此（分别为10,010±1,320和14,710±220mmHg/s，均P<0.05）。总之，LV重量和壁厚度明显增加、LV腔受压以及LV功能障碍反映了人类婴儿型庞贝氏病的心脏异常，尽管不如人类明显，这些小鼠是进一步研究庞贝氏病病理生理学和新疗法的合适模型。
