Cardiac hypertrophy in anion exchanger 1-null mutant mice with severe hemolytic anemia.
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.
Alvarez
Bernardo V
BV
Dept of Physiology, CIHR Membrane Protein Research Group, Univ of Alberta, Edmonton, Alberta, Canada.
Kieller
Dawn M
DM
Quon
Anita L
AL
Robertson
Murray
M
Casey
Joseph R
JR
D000743:Anemia, Hemolytic / Q000150:complications / Q000235:genetics*; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000172:deficiency*; D001835:Body Weight; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D004452:Echocardiography; D004910:Erythrocyte Membrane / Q000502:physiology; D006321:Heart / Q000033:anatomy & histology; D006331:Heart Diseases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001457:Anion Exchange Protein 1, Erythrocyte; D017931:DNA Primers; D012313:RNA; D004247:DNA