Cardiac hypertrophy in anion exchanger 1-null mutant mice with severe hemolytic anemia
Cardiac hypertrophy in anion exchanger 1-null mutant mice with severe hemolytic anemia
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DOI：
10.1152/ajpheart.00449.2006
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发表时间：
2007-03-01
影响因子：
4.8
通讯作者：
Casey, Joseph R.
中科院分区：
文献类型：
--
作者：
Alvarez, Bernardo V.;Kieller, Dawn M.;Casey, Joseph R.
阴离子交换器1（AE 1; SLC 4A 1），红细胞的质膜Cl-/HCO 3-交换器，也在心脏中表达。本研究的目的是通过研究AE 1-null（AE 1（-/-））小鼠来评估AE 1在心脏功能中的作用，这些小鼠表现出由红细胞脆性引起的严重溶血性贫血。在出生后1-3天，AE 1（-/-）小鼠的心脏重量/体重比显著高于野生型（AE 1（+/+））同窝小鼠（3.01 +/- 0.38 vs. 1.45 +/- 0.04）和出生后7天（9.45 +/- 0.53 vs. 4.13 +/- 0.41），表明AE 1缺失导致心脏肥大。杂合子（AE 1（+/-））小鼠无心脏肥大体征。成人AE 1（-/-）突变心脏的形态学显示左心室质量增加，伴随着胶原沉积和纤维化增加。M型超声心动图显示AE 1（-/-）心脏功能障碍，包括左室舒张末期和收缩期扩张以及左室质量扩张，与AE 1（+/+）心脏相比。通过实时定量RT-PCR评估，新生AE 1（-/-）突变小鼠肥大心肌中细胞内pH调节机制的表达与AE 1（+/-）和AE 1（+/+）小鼠没有区别。共聚焦免疫荧光显示，在正常小鼠心肌，AE 1是肌膜，而AE 3和slc 26 a6被发现在肌膜和内膜（T小管和肌浆网）。这些结果表明，患有严重溶血性贫血和球形红细胞增多症的AE 1（-/-）小鼠显示心脏肥大和心脏功能受损，这让人想起红细胞遗传性异常患者的发现。没有发现AE 1在心脏功能中的重要作用。
Anion exchanger 1 (AE1; SLC4A1), the plasma membrane Cl-/HCO3- exchanger of erythrocytes, is also expressed in heart. The aim of this study was to assess the role of AE1 in heart function through study of AE1-null (AE1(-/-)) mice, which manifest severe hemolytic anemia resulting from erythrocyte fragility. Heart weight-to-body weight ratios were significantly higher in the AE1(-/-) mice than in wild-type (AE1(+/+)) littermates at both 1-3 days postnatal (3.01 +/- 0.38 vs. 1.45 +/- 0.04) and at 7 days postnatal (9.45 +/- 0.53 vs. 4.13 +/- 0.41), indicating that loss of AE1 led to cardiac hypertrophy. Heterozygous (AE1(+/-)) mice had no signs of cardiac hypertrophy. Morphology of the adult AE1(-/-) mutant heart revealed an increased left ventricular mass, accompanied by increased collagen deposition and fibrosis. M-mode echocardiography revealed dysfunction of the AE1(-/-) hearts, including dilated left ventricle end diastole and systole and expanded left ventricular mass compared with AE1(+/+) hearts. Expression of intracellular pH-regulatory mechanisms in the hypertrophic myocardium of neonate AE1(-/-) mutant mice was indistinguishable from AE1(+/-) and AE1(+/+) mice, as assessed by quantitative real-time RT-PCR. Confocal immunofluorescence revealed that, in normal mouse myocardium, AE1 is sarcolemmal, whereas AE3 and slc26a6 are found both at the sarcolemma and in internal membranes (T tubules and sarcoplasmic reticulum). These results indicate that AE1(-/-) mice, which suffer from severe hemolytic anemia and spherocytosis, display cardiac hypertrophy and impaired cardiac function, reminiscent of findings in patients with hereditary abnormalities of red blood cells. No essential role for AE1 in heart function was found.