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Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
Cardiac hypertrophy in anion exchanger 1-null mutant mice with severe hemolytic anemia
Bernardo V Alvarez1, Dawn M Kieller, Anita L Quon
1Dept of Physiology, CIHR Membrane Protein Research Group, Univ of Alberta, Edmonton, Alberta, Canada.
Insights
Anion exchanger 1 (AE1) deficiency in mice causes severe anemia and cardiac hypertrophy. Despite anemia, AE1 is not essential for heart function, suggesting other factors contribute to cardiac issues in AE1-null mice.
Area of Science:
- Cardiovascular Physiology
- Hematology
- Molecular Biology
Background:
- Anion exchanger 1 (AE1; SLC4A1) facilitates Cl(-)/HCO(3)(-) exchange in erythrocytes and is present in the heart.
- AE1-null (AE1(-/-)) mice exhibit severe hemolytic anemia due to erythrocyte fragility.
Purpose of the Study:
- To investigate the role of AE1 in cardiac function using AE1-null mice.
- To determine if AE1 deficiency contributes to cardiac abnormalities observed in hereditary red blood cell disorders.
Main Methods:
- Comparative analysis of heart weight-to-body weight ratios in AE1(-/-), AE1(+/-), and AE1(+/+) mice.
- Histological examination of adult AE1(-/-) hearts for cardiac hypertrophy, collagen deposition, and fibrosis.
- M-mode echocardiography to assess cardiac function in AE1(-/-) mice.
- Quantitative real-time RT-PCR to evaluate intracellular pH-regulatory gene expression.
- Confocal immunofluorescence microscopy to determine AE1 localization in myocardium.
Main Results:
- AE1(-/-) mice showed significantly higher heart weight-to-body weight ratios, indicating cardiac hypertrophy.
- Adult AE1(-/-) hearts displayed increased left ventricular mass, collagen deposition, and fibrosis.
- Echocardiography revealed impaired cardiac function in AE1(-/-) mice, including ventricular dilation and expanded mass.
- Expression of intracellular pH regulators was similar across AE1 genotypes.
- AE1 was localized to the sarcolemma in normal mouse myocardium.
Conclusions:
- AE1 deficiency in mice leads to cardiac hypertrophy and dysfunction, associated with severe hemolytic anemia and spherocytosis.
- These cardiac findings in AE1(-/-) mice resemble those in patients with hereditary red blood cell abnormalities.
- Despite the observed cardiac phenotype, AE1 does not appear to play an essential role in maintaining normal heart function.
Abstract:
Anion exchanger 1 (AE1; SLC4A1), the plasma membrane Cl(-)/HCO(3)(-) 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.
