Resistance to cardiomyocyte hypertrophy in ae3 −/− mice, deficient in the AE3 Cl−/HCO3 −exchanger

Abstract

BackgroundCardiac hypertrophy is central to the etiology of heart failure. Understanding the molecular pathways promoting cardiac hypertrophy may identify new targets for therapeutic intervention. Sodium-proton exchanger (NHE1) activity and expression levels in the heart are elevated in many models of hypertrophy through protein kinase C (PKC)/MAPK/ERK/p90RSK pathway stimulation. Sustained NHE1 activity, however, requires an acid-loading pathway. Evidence suggests that the Cl−/HCO3− exchanger, AE3, provides this acid load. Here we explored the role of AE3 in the hypertrophic growth cascade of cardiomyocytes.MethodsAE3-deficient (ae3 −/− ) mice were compared to wildtype (WT) littermates to examine the role of AE3 protein in the development of cardiomyocyte hypertrophy. Mouse hearts were assessed by echocardiography. As well, responses of cultured cardiomyocytes to hypertrophic stimuli were measured. pH regulation capacity of ae3 −/− and WT cardiomyocytes was assessed in cultured cells loaded with the pH-sensitive dye, BCECF-AM.Resultsae3 −/− mice were indistinguishable from wild type (WT) mice in terms of cardiovascular performance. Stimulation of ae3 −/− cardiomyocytes with hypertrophic agonists did not increase cardiac growth or reactivate the fetal gene program. ae3 −/− mice are thus protected from pro-hypertrophic stimulation. Steady state intracellular pH (pHi) in ae3 −/− cardiomyocytes was not significantly different from WT, but the rate of recovery of pHi from imposed alkalosis was significantly slower in ae3 −/− cardiomyocytes.ConclusionsThese data reveal the importance of AE3-mediated Cl−/HCO3− exchange in cardiovascular pH regulation and the development of cardiomyocyte hypertrophy. Pharmacological antagonism of AE3 is an attractive approach in the treatment of cardiac hypertrophy.

Carbonic anhydrase inhibitors reduce cardiac dysfunction after sustained coronary artery ligation in rats

“…Recently, it was demonstrated that AE3 gene deletion prevents cardiomyocyte hypertrophy and reduces the rate of pHi recovery in cardiomyocytes, reinforcing the importance of AE3 in cardiovascular pH regulation and the development of cardiomyocyte hypertrophy [45]. To interfere with the hypertrophic cascade present in heart failure we propose that CAs represent targets for anti-hypertrophic therapy.…”

Population Structure, and Selection Signatures Underlying High-Altitude Adaptation Inferred From Genome-Wide Copy Number Variations in Chinese Indigenous Cattle

“…SLC4A3 encodes a plasma membrane Cl -/HCO 3 exchanger AE3, which belongs to the anion exchanger Solute Carrier Family 4 (SLC4) (Alper et al, 2002;Thorsen et al, 2017). The SLC4A3 knockout mice exhibit normal respiratory response to changes in ambients O 2 or CO 2 but resistance to cardiomyocyte hypertrophy compared to wildtype littermates (Kampik et al, 2014;Sowah et al, 2014). The loss of heterozygosity at SLC4A3 gene locus happened only in high-altitude cattle in current study, which may benefit in resisting the right-ventricle hypertrophy and maitaining healthy heart function under hypoxia.…”

Emerging therapeutic targets in the short QT syndrome

“…However, there is no current pharmacological approach that could restore normal function of mutant AE3. AE3 -/knockout mice have been reported to have similar cardiac function to WT controls at baseline [121;122] and, whilst steady-state pH i was reported to be similar between WT and AE3 -/cardiomyocytes, the knockout myocytes were slower to recover from induced alkalosis [122]. Repolarisation mechanisms differ markedly between mouse and human, however, making mice unsuitable to explore AE3 in the context of SQTS.…”