Cardiac hypertrophy in anion exchanger 1-null mutant mice with severe hemolytic anemia

Abstract

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.

Hypoxia Induces Myocardial Regeneration in Zebrafish

“…6,32-40 Furthermore, we were able to identify genes within the upregulated group that have a heart-associated function (the Table) such as thbs4b, jak2a, txnipa, pim1, slc4a1a, and cxcr4b. 39,[41][42][43][44][45] A number of proproliferative genes were also shown to be upregulated in the wild-type sample compared with the dnHIF1␣ sample (the Table). 46 -51 Although the positive aspects of dedifferentiation have not been intensely investigated, we were able to identify a couple of genes that have been linked to this phenomenon, namely jak2a and cxcr4b, albeit these are most commonly associated with cancer cell dedifferentiation.…”

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

“…545. 31 Bachmann et al cite unpublished observations from Aventis Laboratories that S0859 blocks NBCe1 with a K i ϳ6 M, but does not block NBC2/3 (i.e., NDCBE) as expressed in CHO cells. 32 The use of S0859 as an "NBC1 blocker" (849) or an "NBCn1 inhibitor" (546) in cells in which these transporters are the dominant NCBT paralog does not constitute a demonstration of paralog specificity of the compound.…”

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

“…Ae1 -/-mice exhibit a dilated, fibrotic cardiomyopathy with increased heart weight to body weight ratio in the setting of runting and increased left ventricular mass), but compensatory changes in mRNA levels of alternate regulators of pH i were absent (Alvarez et al, 2007b). The accompanying high-output cardiac insufficiency is likely secondary to severe hemolysis and resultant oxidative stress.…”